Compositions and methods for treatment

Abstract

The present invention provides compounds and methods for the treatment of LFA-1 mediated diseases. In particular, LFA-1 antagonists are described herein and these antagonists are used in the treatment of LFA-1 mediated diseases. One aspect of the invention provides for diagnosis of an LFA-1 mediated disease and administration of a LFA-1 antagonist, after the patient is diagnosed with a LFA-1 mediated disease. In some embodiments, the LFA-1 mediated diseases treated are dry eye disorders. Also provided herein are methods for identifying compounds which are LFA-1 antagonists.

1 .- 101 . (canceled) 
     
     
         102 . A pharmaceutical formulation comprising an LFA-1 antagonist or a pharmaceutically acceptable salt or ester thereof, and an excipient formulated for topical administration. 
     
     
         103 . The formulation of  claim 102 , wherein the LFA-1 antagonist comprises a compound of Formula 1 or its pharmaceutically acceptable salts or esters, wherein 
       
         
           
           
               
               
           
         
         R 1  and R 2  are each independently hydrogen, an amino acid side chain, —(CH 2 ) m OH, —(CH2) m aryl, —(CH2) m heteroaryl, wherein m is 0-6, —CH(R 1A )(OR 1B ), —CH(R 1A )(NHR 1B ), U-T-Q, or an aliphatic, alicyclic, heteroaliphatic or heteroalicyclic moiety optionally substituted with U-T-Q; 
         wherein U is absent, —O—, —S(O) 0-2 —, —SO 2 N(R 1A ), —N(R 1A )—, —N(R 1A )C(═O)—, —N(R 1A )C(═O)—O—, —N(R 1A )C(═O)—N(R 1B )—, —N(R 1A )—SO 2 —, —C(═O)—, —C(═O)—O—, —O—C(═O)—, aryl, heteroaryl, alkylaryl, alkylheteroaryl, —C(═O)—N(R 1A )—, —OC(═O)N(R 1A )—, —C(═N—R 1E )—, —C(═N—R 1E )—O—, —C(═N—R 1E )—N(R 1A )—, —O—C(═N—R 1E )—N(R 1A )—, —N(R 1A )C(═N—R 1E )—, —N(R 1A )C(═N—R 1E )—O—, —N(R 1A )C(═N—R 1E )—N(R 1B )—, —P(═O)(OR 1A )—O—, or —P(═O)(R 1A )—O—; 
         T is absent, an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and 
         Q is hydrogen, halogen, cyano, isocyanate, —OR 1B ; —SR 1B ; —N(R 1B ) 2 , —NHC(═O)OR 1B , —NHC(═O)N(R 1B ) 2 , —NHC(═O)R 1B , —NHSO 2 R 1B , NHSO 2 N(R 1B ) 2 , —NHSO 2 NHC(═O)OR 1B , —NHC(═O)NHSO 2 R 1B , —C(═O)NHC(═O)OR 1B , C(═O)NHC(═O)R 1B , —C(═O)NHC(═O)N(R 1B ) 2 , —C(═O)NHSO 2 R 1B , —C(═O)NHSO 2 N(R 1B ) 2 , C(═S)N(R 1B ) 2 , —SO 2 R 1B , —SO 2 N(R 1B ) 2 , —SO 2 —NHC(═O)OR 1B , —OC(═O)—N(R 1B )2, —OC(═O)R 1B , —OC(═O)NHC(═O)R 1B , —OC(═O)NHSO 2 R 1B , —OSO 2 R 1B , or an aliphatic heteroaliphatic, aryl or heteroaryl moiety, or wherein R 1  and R 2  taken together are an alicyclic or heterocyclic moiety, or together are 
       
       
         
           
           
               
               
           
         
         wherein each occurrence of R 1A  and R 1B  is independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, —C(═O)R 1C , or —C(═O)NR 1C R 1D ; wherein each occurrence of R 1C  and R 1D  is independently hydrogen, hydroxyl, or an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and R 1E  is hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, —CN, —OR 1C , —NR 1C R 1D  or —SO2R 1C ; 
         R 3  is C(═O)OR 3A , —C(═O)H, —CH 2 OR 3A , —CH 2 OC(═O)-alkyl, —C(═O)NH(R 3A ). —CH 2 X 0 ; wherein each occurrence of R 3A  is independently hydrogen, a protecting group, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl heteroalkylheteroaryl moiety, or pharmaceutically acceptable salt or ester, or R 3A , taken together with R 1  and R 2 , forms a heterocyclic moiety; wherein X 0  is a halogen selected from F, Br or I; 
         R 4  for each occurrence, is independently hydrogen, halogen, —CN, —NO 2 , an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is GR G1  wherein G is —O—, —S—, NR G2 , —CO—, —SO—, —SO 2 —, C(═O)O—, C(═O)NR G2 —, C(═O)—, —NR G2 C(═O)— or —SO 2 NR G2 —, and R G1  and R G2  are independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; 
         n is an integer from 0-4; 
         AR 1  is a monocyclic or polycyclic aryl, heteroaryl, alkylaryl, alkylheteroaryl, alicyclic or heterocyclic moiety; 
         A, B, D and E are connected by either a single or double bond, as valency permits; wherein each occurrence of A, D and E is independently C═O, CR i R ii , NR i , CR i , N, O, S, —S(═O) or SO 2 ; wherein each occurrence of R i  is independently hydrogen, halogen, —CN, —NO2, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is -GR G1  wherein G is —O—, —S—, —NR G2 , —CO—, —SO—, —C(═O)O—, —C(═O)NR G2 —, —OC(═O)—, —NR G2 C(═O)— or —SO 2 NR G2 —, and R G1  and R G2  are independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or any two adjacent occurrences of taken together, represent an alicyclic, heteroalicyclic, aryl, or heteroaryl moiety; 
         p is an integer from 0-4; and, 
         L is absent or is V—W—X—Y—Z, wherein each occurrence of V, W, X, Y and Z is independently absent, C═O, NR L1 , —O—, —C(R L1 )═, ═C(R L1 )—, —C(R L1 )(R L2 ), C(═N—OR L1 ), C(═NR L1 ), —N═, S(O) 0-2 ; a substituted or unsubstituted C 1-6  alkenylidene or C 2-6  alkenylidine chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C(═O)—, —CO 2 —, —C(═O)C(═O)—, —C(C═O)NR L3 —, —OC(═O)—, —OC(═O) L3 —, —NR L3 NR L4 —, —NR L3 NR L4 C(═O)—, —NR L3 C(═)—, NR L3 CO 2 —, NR L3 C(═O)NR L4 —, —S(═O)—, —SO 2 —, —NR L3 SO 2 —, —SO 2 NR L3 , —NR L3 SO 2 NR L4 , —O—, —S—, or —NR L3 —; wherein each occurrence of R L3  and R L4  is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl or acyl; or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and each occurrence of R L1  and R L2  is independently hydrogen, hydroxyl, protected hydroxyl, amino, protected amino, thio, protected thio, halogen, cyano, isocyanate, carboxy, carboxyalkyl, formyl, formyloxy, azido, nitro, ureido, thioureido, thiocyanato, alkoxy, aryloxy, mercapto, sulfonamido, benzamido, tosyl, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or wherein one or more occurrences of R L1  and R L2 , taken together, or taken together with one of V, W, X, Y or Z form an alicyclic or heterocyclic moiety or form an aryl or heteroaryl moiety. 
       
     
     
         104 . The formulation of  claim 103 , wherein the LFA-1 antagonist comprises a compound of Formula 1′ and/or its pharmaceutically acceptable salts or esters, having the following structures: 
       
         
           
           
               
               
           
         
         Wherein R 1  and R 2  are each independently hydrogen, an amino acid side chain, —(CH 2 ) m OH, —(CH 2 ) m aryl, —(CH 2 ) m heteroaryl, wherein m is 0-6, —CH(R 1A )(OR 1B ), —CH(R 1A )(NHR 1B ), U-T-Q, or an aliphatic, alicyclic, heteroaliphatic or heteroalicyclic moiety optionally substituted with U-T-Q, wherein U is absent, —O—, —S(O) 0-2 —, —SO 2 N(R 1A ), —N(R 1A )—, —N(R 1A )C(═O)—, —N(R 1A )C(═O)—O—, —N(R 1A )C(═O)—N(R 1B )—, —N(R 1A )—SO 2 —, —C(═O)—, —C(═O)—O—, —O—C(═O)—, aryl, heteroaryl, alkylaryl, alkylheteroaryl, —C(═O)—N(R 1A )—, —OC(═O)N(R 1A )—, —C(═N—R 1E )—, —C(═N—R 1E )—O—, —C(═N—R 1E )—N(R 1A )—, —O—C(═N—R 1E )—N(R 1A )—, —N(R 1A )C(═N—R 1E )—, —N(R 1A )C(═N—R 1E )—O—, —N(R 1A )C(═N—R 1E )—N(R 1B )—, —P(═O)(OR 1A )—O—, or —P(═O)(R 1A )—O—; 
         T is absent, an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and 
         Q is hydrogen, halogen, cyano, isocyanate, —OR 1B ; —SR 1B ; —N(R 1B ) 2 , —NHC(═O)OR 1B , —NHC(═O)N(R 1B ) 2 , —NHC(═O)R 1B , —NHSO 2 R 1B , —NHSO 2 N(R 1B ) 2 , —NHSO 2 NHC(═O)OR 1B , —NHC(═O)NHSO 2 R 1B , —C(═O)NHC(═O)OR 1B , —C(═O)NHC(═O)R 1B , —C(═O)NHC(═O)N(R 1B ) 2 , —C(═O)NHSO 2 R 1B , —C(═O)NHSO 2 N(R 1B ) 2 , C(═S)N(R 1B ) 2 , —SO 2 R 1B , —SO 2 OR 1B , —SO 2 N(R 1B ) 2 , —SO 2 —NHC(═O)OR 1B , —OC(═O)—N(R 1B ) 2 , —OC(═O)R 1B , —OC(═O)NHC(═O)R 1B , —OC(═O)NHSO 2 R 1B , —OSO 2 R 1B , or an aliphatic heteroaliphatic, aryl or heteroaryl moiety, or wherein R 1  and R 2  taken together are an alicyclic or heterocyclic moiety, or together are 
       
       
         
           
           
               
               
           
         
         wherein each occurrence of R 1A  and R 1B  is independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, —C(═O)R 1C , or —C(═O)NR 1C R 1D ; wherein each occurrence of R 1C  and R 1D  is independently hydrogen, hydroxyl, or an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and R 1E  is hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, —CN, —OR 1C , —NR 1C R 1D  or —SO 2 R 1C ; 
         R 3  is C(═O)OR 3A , —C(═O)H, —CH 2 OR 3A , —CH 2 C(═O)-alkyl, —C(═O)NH(R 3A ), CH 2 X 0 ; wherein each occurrence of R 3A  is independently hydrogen, a protecting group, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl heteroalkylheteroaryl moiety, or pharmaceutically acceptable salt or ester, or R 3A , taken together with R 1  and R 2 , forms a heterocyclic moiety; wherein X 0  is a halogen selected from F, Br or I; 
         wherein R 4A  and R 4B  are independently a halogen selected from F, Cl, Br or I; and R B1 , R B2  and R E  are independently hydrogen or substituted or unsubstituted lower alkyl. 
         AR 1  is a monocyclic or polycyclic aryl, heteroaryl, alkylaryl, alkylheteroaryl, alicyclic or heterocyclic moiety; and, 
         L is absent or is V—W—X—Y—Z, wherein each occurrence of V, W, X, Y and Z is independently absent, C═O, NR L1 , —O—, —C(R L1 )═, ═C(R L1 )—, —C(R L1 )(R L2 ), C(═N—OR L1 ), C(═NR L1 ), —N═, S(O) 0-2 ; a substituted or unsubstituted C 1-6  alkenylidene or C 2-6  alkenylidine chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C(═O)—, —CO 2 —, —C(═O)C(═O)—, —C(C═O)NR L3 , —OC(═O)—, —OC(═O)NR L3 —, —NR L3 NR L4 —, —NR L3 NR L4 C(═O)—, —NR L3 C(═O)—, NR L3 CO 2 —, NR L3 C(═O)NR L4 , —S(═O)—, —SO 2 —, —NR L3 SO 2 NR L3 , —NR L3 SO 2 NR L4 , —O—, —S—, or —NR L3 —; wherein each occurrence of R L3  and R L4  is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl or acyl; or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and each occurrence of R L1  and R L2  is independently hydrogen, hydroxyl, protected hydroxyl, amino, protected amino, thio, protected thio, halogen, cyano, isocyanate, carboxy, carboxyalkyl, formyl, formyloxy, azido, nitro, ureido, thioureido, thiocyanato, alkoxy, aryloxy, mercapto, sulfonamido, benzamido, tosyl, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or wherein one or more occurrences of R L1  and R L2 , taken together, or taken together with one of V, W, X, Y or Z form an alicyclic or heterocyclic moiety or form an aryl or heteroaryl moiety. 
       
     
     
         105 . The formulation of  claim 104 , wherein the LFA-1 antagonist has one of the following formulae: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         106 . The formulation of  claim 102  wherein said LFA-1 antagonist comprises a compound of Formula V and its pharmaceutically acceptable salts or esters, wherein 
       
         
           
           
               
               
           
         
         R 14  is a group of the formula 
       
       
         
           
           
               
               
           
         
         R 15  is hydrogen, carboxy, or lower alkyl; 
         U 3 , V 3 , and W 3  are independently hydrogen, halogen; or U 3 , V 3 , and W 3  are lower alkyl provided that U 3  and V 3  are not both hydrogen; 
         X 4  is carbonyl, phenyl-substituted lower alkylene, imino, substituted imino, or sulfonyl; 
         Y 3  is lower alkenylene, lower alkylenethio, or is lower alkylene which may be substituted by amino, acetylamino, or cyclo-lower alkyl; 
         k 2  is 0 or 1; when k 2  is 1, Z is hydrogen, lower alkylthio, —COOH, —CONH 2 —, or amino; 
         when k 2  is 0 or 1, Z 3  is 1-adamantyl, diphenylmethyl, 3-[[(5-chloropyridin-2-yl)amino]carbonyl]pyrazin-2-yl; when k 2  is 0 or 1, Z is cycloalkyl or aryl containing 0 to 3 heteroatoms which may be the same or different, or a fused ring system containing two or three rings which rings are independently cycloalkyl or aryl containing 0 to 3 heteroatoms which may be the same or different, any of which rings may be unsubstituted, or substituted with at least one of halogen, cyano, amino, substituted amino, aminosulfonyl, nitro, oxo, hydroxy, aryl, aryloxy, unsubstituted lower alkyl, halogen-substituted lower alkyl, lower alkoxy-substituted lower alkyl, lower alkoxy, carboxy, alkoxycarbonyl, or acetoxy; and, 
         R 21  is hydrogen, a pharmaceutically acceptable salt or ester. 
       
     
     
         107 . The formulation of  claim 106 , wherein the LFA-1 antagonist has the following formulae: 
       
         
           
           
               
               
           
         
       
     
     
         108 . The formulation of  claim 102 , wherein the daily dosage ranges from about 1×10 −7  g to about 5 g. 
     
     
         109 . The formulation of  claim 102 , wherein the LFA-1 antagonist is a directly competitive antagonist. 
     
     
         110 . The formulation of  claim 102 , wherein the LFA-1 antagonist is a sodium, potassium, lithium, magnesium, or calcium salt. 
     
     
         111 . The formulation of  claim 102 , wherein the formulation is in the form of a gel, cream, lotion, solution, suspension, emulsion, ointment, powder, crystalline forms, spray, foam, aerosol, salve, liposomes, liquid wash, liquid drops, or liquid suspension. 
     
     
         112 . The formulation of  claim 102 , wherein the excipient is selected from the group consisting of humectants, glycols, alcohols, fatty acids, surfactants, pyrrolidones, glycerol monolaurate, sulfoxides, terpenes, amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, polymers such as polyethylene glycols, and combinations thereof. 
     
     
         113 . The formulation of  claim 102 , further comprising a topical penetration enhancer. 
     
     
         114 . The formulation of  claim 102 , further comprising at least one additional therapeutic agent. 
     
     
         115 . The formulation of  claim 105 , wherein the LFA-1 antagonist is a compound having the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         116 . A method for treatment of an inflammatory or immune related disorder in a subject comprising topically administering to said subject in need thereof a formulation comprising an LFA-1 antagonist or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable excipient. 
     
     
         117 . The method of  claim 116 , wherein the LFA-1 antagonist comprises a compound of Formula 1 or its pharmaceutically acceptable salts or esters, wherein 
       
         
           
           
               
               
           
         
         R 1  and R 2  are each independently hydrogen, an amino acid side chain, —(CH 2 ) m OH, —(CH 2 ) m aryl, —(CH 2 ) m heteroaryl, wherein m is 0-6, —CH(R 1A )(OR 1B ), —CH(R 1A )(NHR 1B ), U-T-Q, or an aliphatic, alicyclic, heteroaliphatic or heteroalicyclic moiety optionally substituted with U-T-Q; 
         wherein U is absent, —O—, —S(O) 0-2 —, —SO 2 N(R 1A ), —N(R 1A )—, —N(R 1A )C(═O)—, —N(R 1A )C(═O)—O—, —N(R 1A )C(═O)—N(R 1B )—, —N(R 1A )—SO 2 —, —C(═O)—, —C(═O)—O—, —O—C(═O)—, aryl, heteroaryl, alkylaryl, alkylheteroaryl, —C(═O)—N(R 1A )—, —OC(═O)N(R 1A )—, —C(═N—R 1E )—, —C(═N—R 1E )—O—, —C(═N—R 1E )—N(R 1A )—, —O—C(═N—R 1E )—N(R 1A )—, —N(R 1A )C(═N—R 1E )—, —N(R 1A )C(═N—R 1E )—O—, —N(R 1A )C(═N—R 1E )—N(R 1B )—, —P(═O)(OR 1A )—O—, or —P(═O)(R 1A )—O—; 
         T is absent, an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and 
         Q is hydrogen, halogen, cyano, isocyanate, —OR 1B ; —SR 1B ; —N(R 1B ) 2 , —NHC(═O)OR 1B , —NHC(═O)N(R 1B ) 2 , —NHC(═O)R 1B , —NHSO 2 R 1B , NHSO 2 N(R 1B ) 2 , —NHSO 2 NHC(═O)OR 1B , —NHC(═O)NHSO 2 R 1B , —C(═O)NHC(═O)OR 1B , C(═O)NHC(═O)R 1B , —C(═O)NHC(═O)N(R 1B ) 2 , —C(═O)NHSO 2 R 1B , —C(═O)NHSO 2 N(R 1B ) 2 , C(═S)N(R 1 B) 2 , —SO 2 R 1B , —SO 2 N(R 1B ) 2 , —SO 2 —NHC(═O)OR 1B , —OC(═O)—N(R 1B ) 2 , —OC(═O)R 1B , —OC(═O)NHC(═O)R 1B , —OC(═O)NHSO 2 R 1B , —OSO 2 R 1B , or an aliphatic heteroaliphatic, aryl or heteroaryl moiety, or wherein R 1  and R 2  taken together are an alicyclic or heterocyclic moiety, or together are 
       
       
         
           
           
               
               
           
         
         wherein each occurrence of R 1A  and R 1B  is independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, —C(═O)R 1C , or C(═O)NR 1C R 1D ; wherein each occurrence of R 1C  and R 1D  is independently hydrogen, hydroxyl, or an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and R 1E  is hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, —CN, —OR 1C , —NR 1C R 1D  or —SO2R 1C ; 
         R 3  is C(═O)OR 3A , —C(═O)H, —CH 2 OR 3A , —CH 2 OC(═O)-alkyl, —C(═O)NH(R 3A ). —CH 2 X 0 ; wherein each occurrence of R 3A  is independently hydrogen, a protecting group, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl heteroalkylheteroaryl moiety, or pharmaceutically acceptable salt or ester, or R 3A , taken together with R 1  and R 2 , forms a heterocyclic moiety; wherein X 0  is a halogen selected from F, Br or I; 
         R 4  for each occurrence, is independently hydrogen, halogen, —CN, —NO 2 , an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is GR G1  wherein G is —O—, —S—, NR G2 —, —CO—, —SO—, —SO 2 —, C(═O)O—, —C(═O)NR G2 —, C(═O)—, —NR G2 C(═O)— or —SO 2 NR G2 —, and R G1  and R G2  are independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; 
         n is an integer from 0-4; 
         AR 1  is a monocyclic or polycyclic aryl, heteroaryl, alkylaryl, alkylheteroaryl, alicyclic or heterocyclic moiety; 
         A, B, D and E are connected by either a single or double bond, as valency permits; wherein each occurrence of A, D and E is independently C═O, CR i R ii , NR i , CR i , N, O, S, —S(═O) or SO 2 ; wherein each occurrence of R i  is independently hydrogen, halogen, —CN, —NO2, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is -GR G1  wherein G is —O—, —S—, —NR G2 , —CO—, —SO—, —C(═O)O—, —C(═O)NR G2 —, —OC(═O)—, —NR G2 C(═O)— or —SO 2 NR G2 —, and R G1  and R G2  are independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or any two adjacent occurrences of taken together, represent an alicyclic, heteroalicyclic, aryl, or heteroaryl moiety; 
         p is an integer from 0-4; and, 
         L is absent or is V—W—X—Y—Z, wherein each occurrence of V, W, X, Y and Z is independently absent, C═O, NR L1 , —O—, —C(R L1 )═, ═C(R L1 )—, —C(R L1 )(R L2 ), C(═N—OR L1 ), C(═NR L1 ), —N═, S(O) 0-2 ; a substituted or unsubstituted C 1-6  alkenylidene or C 2-6  alkenylidine chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C(═O)—, —CO 2 —, —C(═O)C(═O)—, —C(C═O)NR L3 —, —OC(═O)—, —OC L3 —, —NR L3 NR L4 —, —NR L3 NR L4 C(═O)—, —NR L3 C(═O)—, NR L3 CO 2 —, NR L3 C(═O)NR L4 —, —S(═O)—, —SO 2 —, —NR L3 SO 2 —, —SO 2 NR L3 , —NR L3 SO 2 NR L4 , —O—, —S—, or —NR L3 —; wherein each occurrence of R L3  and R L4  is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl or acyl; or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and each occurrence of R L1  and R L2  is independently hydrogen, hydroxyl, protected hydroxyl, amino, protected amino, thio, protected thio, halogen, cyano, isocyanate, carboxy, carboxyalkyl, formyl, formyloxy, azido, nitro, ureido, thioureido, thiocyanato, alkoxy, aryloxy, mercapto, sulfonamido, benzamido, tosyl, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or wherein one or more occurrences of R L1  and R L2 , taken together, or taken together with one of V, W, X, Y or Z form an alicyclic or heterocyclic moiety or form an aryl or heteroaryl moiety. 
       
     
     
         118 . The method of  claim 117 , wherein the LFA-1 antagonist comprises a compound of Formula 1′ and/or its pharmaceutically acceptable salts or esters, having the following structures: 
       
         
           
           
               
               
           
         
         Wherein R 1  and R 2  are each independently hydrogen, an amino acid side chain, —(CH 2 ) m OH, —(CH 2 ) m aryl, —(CH 2 ) m heteroaryl, wherein m is 0-6, —CH(R 1A )(OR 1B ), —CH(R 1A )(NHR 1B ), U-T-Q, or an aliphatic, alicyclic, heteroaliphatic or heteroalicyclic moiety optionally substituted with U-T-Q, 
         wherein U is absent, —O—, —S(O) 0-2 —, —SO 2 N(R 1A ), —N(R 1A )—, —N(R 1A )C(═O)—, —N(R 1A )C(═O)—O—, —N(R 1A )C(═O)—N(R 1B )—, —N(R 1A )—SO 2 —, —C(═O)—, —C(═O)—O—, —O—C(═O)—, aryl, heteroaryl, alkylaryl, alkylheteroaryl, —C(═O)—N(R 1A )—, —OC(═O)N(R 1A )—, —C(═N—R 1E )—, —C(═N—R 1E )—O—, —C(═N—R 1E )—N(R 1A )—, —O—C(═N—R 1E )—N(R 1A )—, —N(R 1A )C(═N—R 1E )—, —N(R 1A )C(═N—R 1E )—O—, —N(R 1A )C(═N—R 1E )—N(R 1B )—, —P(═O)(OR 1A )—O—, or —P(═O)(R 1A )—O—; 
         T is absent, an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and 
         Q is hydrogen, halogen, cyano, isocyanate, —OR 1B ; —SR 1B ; —N(R 1B ) 2 , —NHC(═O)OR 1B , —NHC(═O)N(R 1B ) 2 , —NHC(═O)R 1B , —NHSO 2 R 1B , —NHSO 2 N(R 1B ) 2 , —NHSO 2 NHC(═O)OR 1B , —NHC(═O)NHSO 2 R 1B , —C(═O)NHC(═O)OR 1B , —C(═O)NHC(═O)R 1B , —C(═O)NHC(═O)N(R 1B ) 2 , —C(═O)NHSO 2 R 1B , —C(═O)NHSO 2 N(R 1B ) 2 , C(═S)N(R 1B ) 2 , —SO 2 R 1B , —SO 2 OR 1B , —SO 2 N(R 1B ) 2 , —SO 2 —NHC(═O)OR) 1B , —OC(═O)—N(R 1B ) 2 , —OC(═O)R 1B , —OC(═O)NHC(═O)R 1B , —OC(═O)NHSO 2 R 1B , —OSO 2 R 1B , or an aliphatic heteroaliphatic, aryl or heteroaryl moiety, or wherein R 1  and R 2  taken together are an alicyclic or heterocyclic moiety, or together are 
       
       
         
           
           
               
               
           
         
         wherein each occurrence of R 1A  and R 1B  is independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, —C(═O)R 1C , or —C(═O)NR 1C R 1D ; wherein each occurrence of R 1C  and R 1D  is independently hydrogen, hydroxyl, or an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and R 1E  is hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, —CN, —OR 1C , —NR 1C R 1D  or —SO 2 R 1C ; 
         R 3  is C(═O)OR 3A , —C(═O)H, —CH 2 OR 3A , —CH 2 C(═O)-alkyl, —C(═O)NH(R 3A ), CH 2 X 0 ; wherein each occurrence of R 3A  is independently hydrogen, a protecting group, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl heteroalkylheteroaryl moiety, or pharmaceutically acceptable salt or ester, or R 3A , taken together with R 1  and R 2 , forms a heterocyclic moiety; wherein X 0  is a halogen selected from F, Br or I; 
         wherein R 4A  and R 4B  are independently a halogen selected from F, Cl, Br or I; and R B1 , R B2  and R E  are independently hydrogen or substituted or unsubstituted lower alkyl. 
         AR 1  is a monocyclic or polycyclic aryl, heteroaryl, alkylaryl, alkylheteroaryl, alicyclic or heterocyclic moiety; and, 
         L is absent or is V—W—X—Y—Z, wherein each occurrence of V, W, X, Y and Z is independently absent, C═O, NR L1 , —O—, —C(R L1 )═, ═C(R L1 )—, —C(R L1 )(R L2 ), C(═N—OR L1 ), C(═NR L1 ), —N═, S(O) 0-2 ; a substituted or unsubstituted C 1-6  alkenylidene or C 2-6  alkenylidine chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C(═O)—, —CO 2 —, —C(═O)C(═O)—, —C(C═O)NR L3 —, —OC(═O)—, —OC(═O)NR L3 —, —NR L3 NR L4 —, —NR L3 NR L4 C(═O)—, —NR L3 C(═O)—, NR L3 CO 2 —, NR L3 C(═O)NR L4 , —S(═O)—, —SO 2 —, —NR L3 SO 2 , —SO 2 NR L3 , —NR L3 SO 2 NR L4 , —O—, —S—, or —NR L3 —; wherein each occurrence of R L3  and R L4  is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl or acyl; or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and each occurrence of R L1  and R L2  is independently hydrogen, hydroxyl, protected hydroxyl, amino, protected amino, thio, protected thio, halogen, cyano, isocyanate, carboxy, carboxyalkyl, formyl, formyloxy, azido, nitro, ureido, thioureido, thiocyanato, alkoxy, aryloxy, mercapto, sulfonamido, benzamido, tosyl, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or wherein one or more occurrences of R L1  and R L2 , taken together, or taken together with one of V, W, X, Y or Z form an alicyclic or heterocyclic moiety or form an aryl or heteroaryl moiety. 
       
     
     
         119 . The method of  claim 118 , wherein the LFA-1 antagonist has one of the following formulae: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         120 . The method of  claim 116  wherein said LFA-1 antagonist comprises a compound of Formula V and its pharmaceutically acceptable salts or esters, wherein 
       
         
           
           
               
               
           
         
         R 14  is a group of the formula 
       
       
         
           
           
               
               
           
         
         R 15  is hydrogen, carboxy, or lower alkyl; 
         U 3 , V 3 , and W 3  are independently hydrogen, halogen; or U 3 , V 3 , and W 3  are lower alkyl provided that U 3  and V 3  are not both hydrogen; 
         X 4  is carbonyl, phenyl-substituted lower alkylene, imino, substituted imino, or sulfonyl; 
         Y 3  is lower alkenylene, lower alkylenethio, or is lower alkylene which may be substituted by amino, acetylamino, or cyclo-lower alkyl; 
         k 2  is 0 or 1; when k 2  is 1, Z is hydrogen, lower alkylthio, —COOH, —CONH 2 —, or amino; 
         when k 2  is 0 or 1, Z 3  is 1-adamantyl, diphenylmethyl, 3-[[(5-chloropyridin-2-yl)amino]carbonyl]pyrazin-2-yl; when k 2  is 0 or 1, Z is cycloalkyl or aryl containing 0 to 3 heteroatoms which may be the same or different, or a fused ring system containing two or three rings which rings are independently cycloalkyl or aryl containing 0 to 3 heteroatoms which may be the same or different, any of which rings may be unsubstituted, or substituted with at least one of halogen, cyano, amino, substituted amino, aminosulfonyl, nitro, oxo, hydroxy, aryl, aryloxy, unsubstituted lower alkyl, halogen-substituted lower alkyl, lower alkoxy-substituted lower alkyl, lower alkoxy, carboxy, alkoxycarbonyl, or acetoxy; and, 
         R 21  is hydrogen, a pharmaceutically acceptable salt or ester. 
       
     
     
         121 . The method of  claim 120 , wherein the LFA-1 antagonist has the following formulae: 
       
         
           
           
               
               
           
         
       
     
     
         122 . The method of  claim 116 , wherein the daily dosage ranges from about 1×10 −7  g to about 5 g. 
     
     
         123 . The method of  claim 116 , wherein the LFA-1 antagonist is a directly competitive antagonist. 
     
     
         124 . The method of  claim 116 , wherein the LFA-1 antagonist is a sodium, potassium, lithium, magnesium, or calcium salt. 
     
     
         125 . The method of  claim 116 , wherein the formulation is in the form of a gel, cream, lotion, solution, suspension, emulsion, ointment, powder, crystalline forms, spray, foam, aerosol, salve, liposomes, liquid wash, liquid drops, or liquid suspension. 
     
     
         126 . The method of  claim 116 , wherein the excipient is selected from the group consisting of humectants, glycols, alcohols, fatty acids, surfactants, pyrrolidones, glycerol monolaurate, sulfoxides, terpenes, amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, polymers such as polyethylene glycols, and combinations thereof. 
     
     
         127 . The method of  claim 116 , further comprising a topical penetration enhancer. 
     
     
         128 . The method of  claim 116 , further comprising at least one additional therapeutic agent. 
     
     
         129 . The method of  claim 119 , wherein the LFA-1 antagonist is a compound having the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         130 . The method of  claim 116 , wherein the formulation is topically applied to skin, eyes, mouth, and nose. 
     
     
         131 . The method of  claim 116 , wherein the inflammatory or immune disorder is keratoconjunctivitis sicca, Sjorgen's syndrome, corneal injury, age-related dry eye, Stevens-Johnson syndrome, congenital alachrima, pharmacological side effects, infection, Riley-Day syndrome, conjunctival fibrosis, eye stress, glandular and tissue destruction, ocular cicatrical pemphogoid, blepharitis, autoimmune and other immunodeficient disorders, allergies, diabetes, lacrimal gland deficiency, lupus, Parkinson's disease, Sjogren's syndrome, rheumatoid arthritis, rosacea, environmental exposure to excessively dry air, airborne particulates, smoke, and smog or the inability to blink. 
     
     
         132 . The method of  claim 116 , wherein the inflammatory or immune disorder is psoriasis, eczema, asthma, dermatitis, rheumatoid arthritis, systemic lupus erythematosis (SLE), multiple sclerosis, responses associated with inflammatory bowel disease, Reynaud's syndrome, Sjorgen's disease, juvenile onset diabetes, diabetes mellitus, granulomatosis, CNS inflammatory disorder, multiple organ injury disease, all types of transplantations, including graft versus host or host versus graft disease, HIV and rhinovirus infections, or atherosclerosis.