Compounds and methods for inhibiting nhe-mediated antiport in the treatment of disorders associated with fluid retention or salt overload and gastrointestinal tract disorders

Abstract

The present disclosure is directed to compounds and methods for the treatment of disorders associated with fluid retention or salt overload, such as heart failure (in particular, congestive heart failure), chronic kidney disease, end-stage renal disease, liver disease, and peroxisome proliferator-activated receptor (PPAR) gamma agonist-induced fluid retention. The present disclosure is also directed to compounds and methods for the treatment of hypertension. The present disclosure is also directed to compounds and methods for the treatment of gastrointestinal tract disorders, including the treatment or reduction of pain associated with gastrointestinal tract disorders. The methods generally comprise administering to a mammal in need thereof a pharmaceutically effective amount of a compound, or a pharmaceutical composition comprising such a compound, that is designed to be substantially active in the gastrointestinal (GI) tract to inhibit NHE-mediated antiport of sodium ions and hydrogen ions therein. More particularly, the method comprises administering to a mammal in need thereof a pharmaceutically effective amount of a compound, or a pharmaceutical composition comprising such a compound, that inhibits NHE-3, -2 and/or -8 mediated antiport of sodium and/or hydrogen ions in the GI tract and is designed to be substantially impermeable to the layer of epithelial cells, or more specifically the epithelium of the GI tract. As a result of the compound being substantially impermeable, it is not absorbed and is thus essentially systemically non-bioavailable, so as to limit the exposure of other internal organs (e.g., liver, heart, brain, etc.) thereto. The present disclosure is still further directed to a method wherein a mammal is administered such a compound with a fluid-absorbing polymer, such that the combination acts as described above and further provides the ability to sequester fluid and/or salt present in the GI tract.

What is claimed is: 
     
         1 . A compound having:
 (i) a tPSA of at least about 200 Å 2  and a molecular weight of at least about 710 Daltons in the non-salt form; or   (ii) a tPSA of at least about 270 Å 2 ,   wherein the compound is substantially active in the gastrointestinal tract to inhibit NHE-mediated antiport of sodium ions and hydrogen ions therein upon administration to a patient in need thereof.   
     
     
         2 . A compound of  claim 1  wherein the compound has a molecular weight of at least about 500 Da. 
     
     
         3 . A compound of  claim 1  or  2  wherein the compound has a molecular weight of at least about 1000 Da. 
     
     
         4 . A compound of any of  claims 1 - 3  wherein the compound has a molecular weight of at least about 2500 Da. 
     
     
         5 . A compound of any of  claims 1 - 4  wherein the compound has a molecular weight of at least about about 5000 Da. 
     
     
         6 . A compound of any of  claims 1 - 5  wherein the compound has a tPSA of at least about 250 Å 2 . 
     
     
         7 . A compound of any of  claims 1 - 6  wherein the compound has a tPSA of at least about 270 Å 2 . 
     
     
         8 . A compound of any of  claims 1 - 7  wherein the compound has a tPSA of at least about 300 Å 2 . 
     
     
         9 . A compound of any of  claims 1 - 8  wherein the compound has a tPSA of at least about 350 Å 2 . 
     
     
         10 . A compound of any of  claims 1 - 9  wherein the compound has a tPSA of at least about 400 Å 2 . 
     
     
         11 . A compound of any of  claims 1 - 10  wherein the compound has a tPSA of at least about 500 Å 2 . 
     
     
         12 . A compound of any of  claims 1 - 11  wherein the compound is substantially active on the apical side of the epithelium of the gastrointestinal tract to inhibit antiport of sodium ions and hydrogen ions mediated by NHE-3, NHE-2, NHE-8, or a combination thereof. 
     
     
         13 . A compound of any of  claims 1 - 12  wherein the compound is substantially systemically non-bioavailable and/or substantially impermeable to the epithelium of the gastrointestinal tract. 
     
     
         14 . A compound of any of  claims 1 - 13  wherein the compound is substantially active in the lower gastrointestinal tract. 
     
     
         15 . A compound of any of  claims 1 - 14  wherein the compound has (i) a total number of NH and/or OH and/or other potential hydrogen bond donor moieties greater than about 5: (ii) a total number of O atoms and/or N atoms and/or other potential hydrogen bond acceptors greater than about 10; and/or (iii) a Moriguchi partition coefficient greater than about 10 5  or less than about 10. 
     
     
         16 . A compound of any of  claims 1 - 15  wherein the compound has a permeability coefficient, P app  of less than about 100×10 −6  cm/s, or less than about 10×10 −6  cm/s, or less than about 1×10 −6  cm/s, or less than about 0.1×10 −6  cm/s. 
     
     
         17 . A compound of any of  claims 1 - 16  wherein the compound is substantially localized in the gastrointestinal tract or lumen. 
     
     
         18 . A compound of any of  claims 1 - 17  wherein the compound inhibits NHE irreversibly. 
     
     
         19 . A compound of any of  claims 1 - 18  wherein the compound is capable of providing a substantially persistent inhibitory action and wherein the compound is orally administered once-a-day. 
     
     
         20 . A compound of any of  claims 1 - 19  wherein the compound is substantially stable under physiological conditions in the gastrointestinal tract. 
     
     
         21 . A compound of any of  claims 1 - 20  wherein the compound is inert with regard to gastrointestinal flora. 
     
     
         22 . A compound of any of  claims 1 - 21  wherein the compound is designed to be delivered to the lower part of the gastrointestinal tract. 
     
     
         23 . A compound of any of  claims 1 - 22  wherein the compound is designed to be delivered to the lower part of the gastrointestinal tract past the duodenum. 
     
     
         24 . A compound of any of  claims 1 - 23  wherein the compound, when administered at a dose resulting in at least a 10% increase in fecal water content, has a C max  that is less than the IC 50  for NHE-3, less than about 10× the IC 50 , or less than about 100× the IC 50 . 
     
     
         25 . A compound of any of  claims 1 - 24  wherein, upon administration of the compound to a patient in need thereof, the compound exhibits a maximum concentration detected in the serum, defined as C max , that is lower than the NHE inhibitory concentration IC 50  of the compound. 
     
     
         26 . A compound of any of  claims 1 - 24  wherein, upon administration of the compound to a patient in need thereof, greater than about 80%, greater than about 90% or greater than about 95% of the amount of compound administered is present in the patient's feces. 
     
     
         27 . A compound of any of  claims 1 - 26  wherein the compound has a structure of Formula (I) or (IX): 
       
         
           
           
               
               
           
         
         wherein:
 NHE is a NHE-inhibiting small molecule that comprises (i) a hetero-atom containing moiety, and (ii) a cyclic or heterocyclic scaffold or support moiety bound directly or indirectly thereto, the heteroatom-containing moiety being selected from a substituted guanidinyl moiety and a substituted heterocyclic moiety, which may optionally be fused with the scaffold or support moiety to form a fused bicyclic structure; and, 
 Z is a moiety having at least one site thereon for attachment to the NHE-inhibiting small molecule, the resulting NHE-Z molecule possessing overall physicochemical properties that render it substantially impermeable or substantially systemically non-bioavailable; and, 
 E is an integer having a value of 1 or more. 
 
       
     
     
         28 . A compound of  claim 27  wherein the total number of freely rotatable bonds in the NHE-Z molecule is at least about 10. 
     
     
         29 . A compound of  claim 27  or  28  wherein the total number hydrogen bond donors in the NHE-Z molecule is at least about 5. 
     
     
         30 . A compound of any of  claims 27 - 29  wherein the total number of hydrogen bond acceptors in the NHE-Z molecule is at least about 10. 
     
     
         31 . A compound of any of  claims 27 - 30  wherein the total number of hydrogen bond donors and hydrogen bond acceptors in the NHE-Z molecule is at least about 10. 
     
     
         32 . A compound of any of  claims 27 - 31  wherein the Log P of the NHE-Z inhibiting compound is at least about 5. 
     
     
         33 . A compound of any of  claims 27 - 31  wherein the log P of the NHE-Z inhibiting compound is less than about 1, or less than about 0. 
     
     
         34 . A compound of any of  claims 27 - 33  wherein the scaffold is a 5-member or 6-member cyclic or heterocyclic moiety. 
     
     
         35 . A compound of  claim 34  wherein the scaffold is aromatic. 
     
     
         36 . A compound as set forth in any one of  claims 27 - 35 , wherein the scaffold of the NHE-inhibiting small molecule is bound to the moiety, Z, the compound having the structure of Formula (II): 
       
         
           
           
               
               
           
         
         wherein:
 Z is a Core having one or more sites thereon for attachment to one or more NHE-inhibiting small molecules, the resulting NHE-Z molecule possessing overall physicochemical properties that render it substantially impermeable or substantially systemically non-bioavailable; 
 B is the heteroatom-containing moiety of the NHE-inhibiting small molecule, and is selected from a substituted guanidinyl moiety and a substituted heterocyclic moiety, which may optionally be fused with the Scaffold moiety to form a fused, bicyclic structure; 
 Scaffold is the cyclic or heterocyclic scaffold or support moiety of the NHE-inhibiting small molecule, which is bound directly or indirectly to heteroatom-containing moiety, B, and which is optionally substituted with one or more additionally hydrocarbyl or heterohydrocarbyl moieties; 
 X is a bond or a spacer moiety selected from a group consisting of substituted or unsubstituted hydrocarbyl or heterohydrocarbyl moieties, and in particular substituted or unsubstituted C 1-7  hydrocarbyl or heterohydrocarbyl, and substituted or unsubstituted, saturated or unsaturated, cyclic or heterocyclic moieties, which links B and the Scaffold; and, 
 D and E are integers, each independently having a value of 1 or more. 
 
       
     
     
         37 . A compound of any of  claims 27 - 36  wherein the compound is an oligomer, dendrimer or polymer, and further wherein Z is a Core moiety having two or more sites thereon for attachment to multiple NHE-inhibiting small molecules, either directly or indirectly through a linking moiety, L, the compound having the structure of Formula (X):
   CoreL-NHE) n    (X)
 
 wherein L is a bond or linker connecting the Core to the NHE-inhibiting small molecule, and n is an integer of 2 or more, and further wherein each NHE-inhibiting small molecule may be the same or differ from the others. 
 
     
     
         38 . A compound of  claim 37  wherein the NHE-inhibiting small molecule has the structure of Formula (IV): 
       
         
           
           
               
               
           
         
       
       or a stereoisomer, prodrug or pharmaceutically acceptable salt thereof,
 wherein:
 each R 1 , R 2 , R 3 , R 5  and R 9  are independently selected from H, halogen, —NR 7 (CO)R 8 , —(CO)NR 7 R 8 , —SO 2 —NR 7 R 8 , —NR 7 SO 2 R 8 , —NR 7 R 8 , —OR 7 , —SR 7 , —O(CO)NR 7 R 8 , —NR 7 (CO)OR 8 , and —NR 7 SO 2 NR 8 , where R 7  and R 8  are independently selected from H or a bond linking the NHE-inhibiting small molecule to L, provided at least one is a bond linking the NHE-inhibiting small molecule to L; 
 R 4  is selected from H, C 1 -C 7  alkyl, or a bond linking the NHE-inhibiting small molecule to L; 
 R 6  is absent or selected from H and C 1 -C 7  alkyl; and 
 Ar1 and Ar2 independently represent an aromatic ring or a heteroaromatic ring. 
 
 
     
     
         39 . A compound of  claim 38  wherein the NHE-inhibiting small molecule has the following structure: 
       
         
           
           
               
               
           
         
       
       or a stereoisomer, prodrug or pharmaceutically acceptable salt thereof,
 wherein:
 each R 1 , R 2  and R 3  are independently selected from H, halogen, —NR 7 (CO)R 8 , —(CO)NR 7 R 8 , —SO 2 —NR 7 R 8 , —NR 7 SO 2 R 8 , —NR 7 R 8 , —OR 7 , —SR 7 , —O(CO)NR 7 R 8 , —NR 7 (CO)OR 8 , and —NR 7 SO 2 NR 8 , where R 7  and R 8  are independently selected from H or a bond linking the NHE-inhibiting small molecule to L, provided at least one is a bond linking the NHE-inhibiting small molecule to L. 
 
 
     
     
         40 . A compound of  claim 39  wherein the NHE-inhibiting small molecule has one of the following structures: 
       
         
           
           
               
               
           
         
         or a stereoisomer, prodrug or pharmaceutically acceptable salt thereof. 
       
     
     
         41 . A compound of any of  claims 37 - 40  wherein L is a polyalkylene glycol linker. 
     
     
         42 . A compound of any of  claims 37 - 41  wherein L is a polyethylene glycol linker. 
     
     
         43 . A compound of any of  claims 37 - 42  wherein n is 2. 
     
     
         44 . A compound of any of  claims 37 - 43  wherein the Core has the following structure: 
       
         
           
           
               
               
           
         
         wherein:
 X is selected from the group consisting of a bond, —O—, —NH—, —S—, C 1-6 alkylene, —NHC(═O)—, —C(═O)NH—, —NHC(═O)NH—, —SO 2 NH—, and —NHSO 2 —; 
 Y is selected from the group consisting of a bond, optionally substituted C 1-8 alkylene, optionally substituted aryl, optionally substituted heteroaryl, a polyethylene glycol linker, —(CH 2 ) 1-6 O(CH 2 ) 1-6 — and —(CH 2 ) 1-6 NY 1 (CH 2 ) 1-6 —; and 
 Y 1  is selected from the group consisting of hydrogen, optionally substituted C 1-8 alkyl, optionally substituted aryl or optionally substituted heteroaryl. 
 
       
     
     
         45 . A compound of any of  claims 37 - 44  wherein the Core is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         46 . A compound of any of  claims 27 - 36  wherein the compound is an oligomer, and further wherein Z is a linking moiety, L, that links two or more NHE-inhibiting small molecules together, when the two or more NHE-inhibiting small molecules may be the same or different, the compound having the structure of Formula (XI): 
       
         
           
           
               
               
           
         
         wherein L is a bond or linker connecting one NHE-inhibiting small molecule to another, and m is 0 or an integer of 1 or more. 
       
     
     
         47 . A compound of any of  claims 27 - 36  wherein the compound is an oligomer, dendrimer or polymer, and further wherein Z is a backbone, denoted Repeat Unit, to which is bound multiple NHE-inhibiting moieties, the compound having the structure of Formula (XIIB): 
       
         
           
           
               
               
           
         
         wherein: L is a bond or a linking moiety; NHE is a NHE-inhibiting small molecule; and n is a non-zero integer. 
       
     
     
         48 . A pharmaceutical composition comprising a compound of any of  claims 1 - 47 , or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier, diluent or excipient. 
     
     
         49 . A pharmaceutical composition of  claim 48 , further comprising a fluid-absorbing polymer. 
     
     
         50 . A pharmaceutical composition of  claim 49  wherein the fluid-absorbing polymer is delivered directly to the colon. 
     
     
         51 . A pharmaceutical composition of  claim 49  or  50  wherein the fluid-absorbing polymer has a fluid absorbency of at least about 15 g of isotonic fluid per g of polymer under a static pressure of about 5 kPa. 
     
     
         52 . A pharmaceutical composition of any of  claims 49 - 51  wherein the fluid-absorbing polymer has a fluid absorbency of at least about 15 g of isotonic fluid per g of polymer under a static pressure of about 10 kPa. 
     
     
         53 . A pharmaceutical composition of any of  claims 49 - 52  wherein the fluid-absorbing polymer is characterized by a fluid absorbency of at least about 10 g/g. 
     
     
         54 . A pharmaceutical composition of any of  claims 49 - 53  wherein the fluid-absorbing polymer is characterized by a fluid absorbency of at least about 15 g/g. 
     
     
         55 . A pharmaceutical composition of any of  claims 49 - 54  wherein the fluid-absorbing polymer is superabsorbent. 
     
     
         56 . A pharmaceutical composition of any of  claims 49 - 54  wherein the fluid-absorbing polymer is a crosslinked, partially neutralized polyelectrolyte hydrogel. 
     
     
         57 . A pharmaceutical composition of any of  claims 49 - 54  wherein the fluid-absorbing polymer is a crosslinked polyacrylate. 
     
     
         58 . A pharmaceutical composition of any of  claims 49 - 54  wherein the fluid-absorbing polymer is a polyelectrolyte. 
     
     
         59 . A pharmaceutical composition of any of  claims 49 - 54  wherein the fluid-absorbing polymer is calcium Carbophil. 
     
     
         60 . A pharmaceutical composition of any of  claims 49 - 54  wherein the fluid-absorbing polymer is prepared by a high internal phase emulsion process. 
     
     
         61 . A pharmaceutical composition of any of  claims 49 - 54  wherein the fluid-absorbing polymer is a foam. 
     
     
         62 . A pharmaceutical composition of any of  claims 49 - 54  wherein the fluid-absorbing polymer is prepared by a aqueous free radical polymerization of acrylamide or a derivative thereof, a crosslinker and a free radical initiator redox system in water. 
     
     
         63 . A pharmaceutical composition of any of  claims 49 - 54  wherein the fluid-absorbing polymer is a hydrogel. 
     
     
         64 . A pharmaceutical composition of any of  claims 49 - 54  wherein the fluid-absorbing polymer is an N-alkyl acrylamide. 
     
     
         65 . A pharmaceutical composition of any of  claims 49 - 54  wherein the fluid-absorbing polymer is a superporous gel. 
     
     
         66 . A pharmaceutical composition of any of  claims 49 - 54  wherein the fluid-absorbing polymer is naturally occurring. 
     
     
         67 . A pharmaceutical composition of any of  claims 49 - 54  wherein the fluid-absorbing polymer is selected from the group consisting of xanthan, guar, wellan, hemicelluloses, alkyl-cellulose hydro-alkyl-cellulose, carboxy-alkyl-cellulose, carrageenan, dextran, hyaluronic acid and agarose. 
     
     
         68 . A pharmaceutical composition of any of  claims 49 - 54  wherein the fluid-absorbing polymer is  psyllium.    
     
     
         69 . A pharmaceutical composition of any of  claims 49 - 54  wherein the fluid-absorbing polymer is a polysaccharide that includes xylose and arabinose. 
     
     
         70 . A pharmaceutical composition of any of  claims 49 - 54  wherein the fluid-absorbing polymer is a polysaccharide that includes xylose and arabinose, wherein the ratio of xylose to arabinose is at least about 3:1, by weight. 
     
     
         71 . A pharmaceutical composition of any of  claims 49 - 70 , further comprising another pharmaceutically active agent or compound. 
     
     
         72 . A pharmaceutical composition of  claim 71  wherein the composition further comprises another pharmaceutically active agent or compound selected from the group consisting of a diuretic, cardiac glycoside, ACE inhibitor, angiotensin-2 receptor antagonist, calcium channel blocker, beta blocker, alpha blocker, central alpha agonist, vasodilator, blood thinner, anti-platelet agent, lipid-lowering agent, and peroxisome proliferator-activated receptor (PPAR) gamma agonist agent. 
     
     
         73 . A pharmaceutical composition of  claim 72  wherein the diuretic is selected from the group consisting of a high ceiling loop diuretic, a benzothiadiazide diuretic, a potassium sparing diuretic, and a osmotic diuretic. 
     
     
         74 . A pharmaceutical composition of  claim 71  wherein the composition further comprises another pharmaceutically active agent or compound selected from the group consisting of an analgesic peptide or agent. 
     
     
         75 . A pharmaceutical composition of  claim 74  wherein the composition further comprises another pharmaceutically active agent or compound selected from the group consisting of a laxative agent selected from a bulk-producing agent (e.g.  psyllium  husk (Metamucil)), methylcellulose (Citrucel), polycarbophil, dietary fiber, apples, stool softeners/surfactant (e.g., docusate, Colace, Diocto), a hydrating or osmotic agent (e.g., dibasic sodium phosphate, magnesium citrate, magnesium hydroxide (Milk of magnesia), magnesium sulfate (which is Epsom salt), monobasic sodium phosphate, sodium biphosphate), a hyperosmotic agent (e.g., glycerin suppositories, sorbitol, lactulose, and polyethylene glycol (PEG)). 
     
     
         76 . A method for inhibiting NHE-mediated antiport of sodium and hydrogen ions, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound or pharmaceutical composition of any of  claims 1 - 75 . 
     
     
         77 . A method for treating a disorder associated with fluid retention or salt overload, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound or pharmaceutical composition of any of  claims 1 - 75 . 
     
     
         78 . A method for treating a disorder selected from the group consisting of heart failure, chronic kidney disease, end-stage renal disease, liver disease, and peroxisome proliferator-activated receptor (PPAR) gamma agonist-induced fluid retention, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound or pharmaceutical composition of any of  claims 1 - 75 . 
     
     
         79 . The method of  claim 78  wherein the heart failure is congestive heart failure. 
     
     
         80 . A method for treating hypertension, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound or pharmaceutical composition of any of  claims 1 - 75 . 
     
     
         81 . A method of any of  claims 77 - 80  wherein the method comprises administering a pharmaceutically effective amount of the compound to the mammal in order to increase the mammal's daily fecal output of sodium and/or fluid. 
     
     
         82 . A method of any of  claims 77 - 81  wherein the method comprises administering a pharmaceutically effective amount of the compound to the mammal in order to increase the mammal's daily fecal output of sodium by at least about 30 mmol, and/or fluid by at least about 200 ml. 
     
     
         83 . A method of any of  claims 77 - 82  wherein the mammal's fecal output of sodium and/or fluid is increased without introducing another type of cation in a stoichiometric or near stoichiometric fashion via an ion exchange process. 
     
     
         84 . A method of any of  claims 77 - 83 , further comprising administering to the mammal a fluid-absorbing polymer to absorb fecal fluid resulting from the use of the compound that is substantially active in the gastrointestinal tract to inhibit NHE-mediated antiport of sodium ions and hydrogen ions therein. 
     
     
         85 . A method of any of  claims 77 - 84  wherein the compound or composition is administered to treat hypertension. 
     
     
         86 . A method of any of  claims 77 - 85  wherein the compound or composition is administered to treat hypertension associated with dietary salt intake. 
     
     
         87 . A method of any of  claims 77 - 84  wherein administration of the compound or composition allows the mammal to intake a more palatable diet. 
     
     
         88 . A method of any of  claims 77 - 84  wherein the compound or composition is administered to treat fluid overload. 
     
     
         89 . A method of  claim 88  wherein the fluid overload is associated with congestive heart failure. 
     
     
         90 . A method of  claim 88  wherein the fluid overload is associated with end stage renal disease. 
     
     
         91 . A method of  claim 88  wherein the fluid overload is associated with peroxisome proliferator-activated receptor (PPAR) gamma agonist therapy. 
     
     
         92 . A method of any of  claims 77 - 84  wherein the compound or composition is administered to treat sodium overload. 
     
     
         93 . A method of any of  claim 77 - 84  wherein the compound or composition is administered to reduce interdialytic weight gain in ESRD patients. 
     
     
         94 . A method of any of  claims 77 - 84  wherein the compound or composition is administered to treat edema. 
     
     
         95 . A method of any of  claim 94  wherein the edema is caused by chemotherapy, pre-menstrual fluid overload or preeclampsia. 
     
     
         96 . A method of any of  claims 77 - 95  wherein the compound or composition is administered orally, by rectal suppository, or enema. 
     
     
         97 . A method of any one of  claims 77 - 96 , wherein the method comprises administering a pharmaceutically effective amount of the compound or composition in combination with one or more additional pharmaceutically active compounds or agents. 
     
     
         98 . A method of  claim 97  wherein the one or more additional pharmaceutically active compounds or agents is selected from the group consisting of a diuretic, cardiac glycoside, ACE inhibitor, angiotensin-2 receptor antagonist, aldosterone antagonist, calcium channel blocker, beta blocker, alpha blocker, central alpha agonist, vasodilator, blood thinner, anti-platelet agent, lipid-lowering agent, and peroxisome proliferator-activated receptor (PPAR) gamma agonist agent. 
     
     
         99 . A method of  claim 98  wherein the diuretic is selected from the group consisting of a high ceiling loop diuretic, a benzothiadiazide diuretic, a potassium sparing diuretic, and a osmotic diuretic. 
     
     
         100 . A method of any of  claims 97 - 99  wherein the pharmaceutically effective amount of the compound or composition, and the one or more additional pharmaceutically active compounds or agents, are administered as part of a single pharmaceutical preparation. 
     
     
         101 . A method of any of  claims 97 - 99  wherein the pharmaceutically effective amount of the compound or composition, and the one or more additional pharmaceutically active compounds or agents, are administered as individual pharmaceutical preparations. 
     
     
         102 . A method of  claim 101  wherein the individual pharmaceutical preparation are administered sequentially. 
     
     
         103 . A method of  claim 102  wherein the individual pharmaceutical preparation are administered simultaneously. 
     
     
         104 . A method for treating a gastrointestinal tract disorder, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound or pharmaceutical composition of any of  claims 1 - 75 . 
     
     
         105 . A method of  claim 104  wherein the gastrointestinal tract disorder is a gastrointestinal motility disorder. 
     
     
         106 . A method of  claim 104  wherein the gastrointestinal tract disorder is irritable bowel syndrome. 
     
     
         107 . A method of  claim 104  wherein the gastrointestinal tract disorder is chronic constipation. 
     
     
         108 . A method of  claim 104  wherein the gastrointestinal tract disorder is chronic idiopathic constipation. 
     
     
         109 . A method of  claim 104  wherein the gastrointestinal tract disorder is chronic constipation occurring in cystic fibrosis patients. 
     
     
         110 . A method of  claim 104  wherein the gastrointestinal tract disorder is opioid-induced constipation. 
     
     
         111 . A method of  claim 104  wherein the gastrointestinal tract disorder is a functional gastrointestinal tract disorder. 
     
     
         112 . A method of  claim 104  wherein the gastrointestinal tract disorder is selected from the group consisting of chronic intestinal pseudo-obstruction and colonic pseudo-obstruction. 
     
     
         113 . A method of  claim 104  wherein the gastrointestinal tract disorder is Crohn's disease. 
     
     
         114 . A method of  claim 104  wherein the gastrointestinal tract disorder is ulcerative colitis. 
     
     
         115 . A method of  claim 104  wherein the gastrointestinal tract disorder is a disease referred to as inflammatory bowel disease. 
     
     
         116 . A method of  claim 104  wherein the gastrointestinal tract disorder is associated with chronic kidney disease (stage 4 or 5). 
     
     
         117 . A method of  claim 104  wherein the gastrointestinal tract disorder is constipation induced by calcium supplement. 
     
     
         118 . A method of  claim 104  wherein the gastrointestinal tract disorder is constipation, and further wherein the constipation to be treated is associated with the use of a therapeutic agent. 
     
     
         119 . A method of  claim 104  wherein the gastrointestinal tract disorder is constipation, and further wherein the constipation to be treated is associated with a neuropathic disorder. 
     
     
         120 . A method of  claim 104  wherein the gastrointestinal tract disorder is constipation, and further wherein the constipation to be treated is post-surgical constipation (postoperative ileus). 
     
     
         121 . A method of  claim 104  wherein the gastrointestinal tract disorder is constipation, and further wherein the constipation to be treated is idiopathic (functional constipation or slow transit constipation). 
     
     
         122 . A method of  claim 104  wherein the gastrointestinal tract disorder is constipation, and further wherein the constipation to be treated is associated with neuropathic, metabolic or an endocrine disorder (e.g., diabetes mellitus, renal failure, hypothyroidism, hyperthyroidism, hypocalcaemia, Multiple Sclerosis, Parkinson's disease, spinal cord lesions, neurofibromatosis, autonomic neuropathy, Chagas disease, Hirschsprung's disease or cystic fibrosis, and the like). 
     
     
         123 . A method of  claim 104  wherein the gastrointestinal tract disorder is constipation, and further wherein the constipation to be treated is due the use of drugs selected from analgesics (e.g., opioids), antihypertensives, anticonvulsants, antidepressants, antispasmodics and antipsychotics. 
     
     
         124 . A method for treating irritable bowel syndrome, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of an NHE-3 inhibitor compound or a pharmaceutical composition comprising an NHE-3 inhibitor compound. 
     
     
         125 . A method of  claim 124  wherein the NHE-3 inhibitor compound or the pharmaceutical composition comprising an NHE-3 inhibitor compound is a compound or pharmaceutical composition of any of  claims 1 - 75 . 
     
     
         126 . A method of any of  claims 104 - 125  wherein the compound or composition is administered to treat or reduce pain associated with a gastrointestinal tract disorder. 
     
     
         127 . A method of any of  claims 104 - 125  wherein the compound or composition is administered to treat or reduce visceral hypersensitivity associated with a gastrointestinal tract disorder. 
     
     
         128 . A method of any of  claims 104 - 125  wherein the compound or composition is administered to treat or reduce inflammation of the gastrointestinal tract. 
     
     
         129 . A method of any of  claims 104 - 125  wherein the compound or composition is administered to reduce gastrointestinal transit time. 
     
     
         130 . A method of any of  claims 104 - 129  wherein the compound or composition is administered either orally or by rectal suppository. 
     
     
         131 . A method of any of  claims 104 - 130  wherein the method comprises administering a pharmaceutically effective amount of the compound or composition, in combination with one or more additional pharmaceutically active compounds or agents. 
     
     
         132 . A method of  claim 131  wherein the one or more additional pharmaceutically active agents or compounds are an analgesic peptide or agent. 
     
     
         133 . A method of  claim 131  wherein the one or more additional pharmaceutically active agents or compounds are selected from the group consisting of a laxative agent selected from a bulk-producing agent (e.g.  psyllium  husk (Metamucil)), methylcellulose (Citrucel), polycarbophil, dietary fiber, apples, stool softeners/surfactant (e.g., docusate, Colace, Diocto), a hydrating or osmotic agent (e.g., dibasic sodium phosphate, magnesium citrate, magnesium hydroxide (Milk of magnesia), magnesium sulfate (which is Epsom salt), monobasic sodium phosphate, sodium biphosphate), and a hyperosmotic agent (e.g., glycerin suppositories, sorbitol, lactulose, and polyethylene glycol (PEG)). 
     
     
         134 . A method of any of  claims 131 - 133  wherein the pharmaceutically effective amount of the compound or composition, and the one or more additional pharmaceutically active compounds or agents, are administered as part of a single pharmaceutical preparation. 
     
     
         135 . A method of any of  claims 131 - 133  wherein the pharmaceutically effective amount of the compound or composition, and the one or more additional pharmaceutically active compounds or agents, are administered as individual pharmaceutical preparations. 
     
     
         136 . A method of  claim 135  wherein the individual pharmaceutical preparation are administered sequentially. 
     
     
         137 . A method of  claim 135  wherein the individual pharmaceutical preparation are administered simultaneously. 
     
     
         138 . A method of treating a disease associated with paracellular permeability comprising administering an agent which causes intracellular accumulation of protons. 
     
     
         139 . The method of  claim 138 , wherein the agent is an NHE-3 inhibitor. 
     
     
         140 . The method of  claim 138 , wherein the NHE-3 inhibitor is a compound of any one of  claims 1 - 47 . 
     
     
         141 . The method of  claim 138 , wherein the agent is not an NHE-3 inhibitor. 
     
     
         142 . The method of any one of  claims 138 - 141 , wherein the disease is selected from gastrointestinal motility disorder, irritable bowel syndrome, chronic constipation, chronic idiopathic constipation, chronic constipation occurring in cystic fibrosis, opioid-induced constipation, chronic intestinal pseudo-obstruction, colonic pseudo-obstruction, ulcerative colitis, inflammatory bowel disease, gastrointestinal tract disorder is associated with chronic kidney disease (stage 4 or 5), constipation induced by calcium supplement, constipation associated with the use of a therapeutic agent, constipation associated with a neuropathic disorder (Parkinson's disease, multiple sclerosis), post-surgical constipation (postoperative ileus), idiopathic constipation (functional constipation or slow transit constipation), constipation associated with neuropathic, metabolic or an endocrine disorder, constipation due the use of drugs selected from analgesics (e.g., opioids), antihypertensive, anticonvulsants, antidepressants, antispasmodics and antipsychotics, gastric ulcers, infectious diarrhea, leaky gut syndrome, cystic fibrosis gastrointestinal disease, microscopic colitis, necrotizing enterocolitis, atopy, food allergy, acute inflammation, chronic inflammation, obesity-induced metabolic diseases, kidney disease, chronic kidney disease, diabetic kidney disease, heart disease, heart failure, congestive heart failure, hypertension, essential hypertension, primary hypertension, salt-sensitive hypertension, liver disease, cirrhosis, nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, steatosis, primary sclerosing cholangitis, primary biliary cholangitis, portal hypertension, Type 1 diabetes, celiac disease, multiple sclerosis, ankylosing spondylitis, rheumatoid arthritis, lupus, alopecia areata, polymyalgia rheumatica, multiple sclerosis, fibromyalgia, chronic fatigue syndrome, Sjogren's syndrome, vitiligo, thyroiditis, vasculitis, Crohn's disease, ulcerative colitis, urticaria (hives), Raynaud's syndrome, schizophrenia, autism spectrum disorders, multiple sclerosis, hepatic encephalopathy, small intestinal bacterial overgrowth, secondary hyperparathyroidism (PTH), celiac disease, hyperphosphatemia, vascular calcification, elevated FGF-23 levels, cardiac hypertrophy or chronic alcoholism.