Heterocyclic compounds, combinatorial libraries thereof and methods of selecting drug leads

Abstract

Heterocyclic compounds having a relatively flexible backbone are used to create combinatorial libraries that permit screening for lead compounds and selection of drug candidates for a variety of uses in human and veterinary medicine as well as in agriculture. The compounds of the library generally differ in ring size and chirality of substituents on the ring. Also disclosed are methods for providing and screening these libraries, preferably in an automated or computerizable manner, such as by using a computer program to virtually screen the compounds in order to identify those that are predicted to have bioactive conformations that should give rise to desirable biological effects.

1 . A heterocyclic compound represented by the structure of formula I:  
     
       
         
         
             
             
         
       
     
     wherein 
 A, B and D are independently of each other CH 2 , C═O or a bond;  
 X and Y are independently of each other O, S, C═O, S═O, SO 2 , CR 3a R 3b , NR 4  or C═S, or X and Y together form a group represented by the formula:  
                     
 R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a  and R 4b  are independently of each other hydrogen or a linear or branched chain alkyl;  
 m and n are independently of each other an integer of 1-6;  
 Z and Q are independently of each other  
                     
 R 5a , R 5b , R 6a , R 6b , R 7a , R 7b , R 8 , R 9a , and R 9b  are independently of each other hydrogen, a linear or branched chain alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, acyl, carboxyalkyl, carboxyaryl, benzyl, hydroxybenzyl, benzyloxycarbonyl, a side chain of a natural or unnatural amino acid or a peptide;  
 L is hydrogen, OR 10 , or NHR 11  wherein R 10  and R 11  are independently of each other hydrogen, a linear or branched chain alkyl, a side chain of a natural or unnatural amino acid, a peptide or a solid support; and  
                     
 is a heterocyclic moiety containing one or more nitrogens;  
 or a pharmaceutically acceptable salt, hydrate or solvate thereof.  
 
   
   
       2 . The compound according to  claim 1 , wherein A and D are a bond and B is C═O.  
   
   
       3 . The compound according to  claim 1 , wherein A is a bond, B is CH 2  are C is C═O.  
   
   
       4 . The compound according to  claim 1 , wherein Q is  
     
       
         
         
             
             
         
       
     
   
   
       5 . The compound according to  claim 1 , wherein Z is  
     
       
         
         
             
             
         
       
     
   
   
       6 . The compound according to  claim 1 , wherein one of R 5a  and R 5b  is hydrogen and the other is benzyl or hydroxybenzyl.  
   
   
       7 . The compound according to  claim 1 , wherein one of R 6a  and R 6b  is hydrogen and the other is benzyl or hydroxybenzyl.  
   
   
       8 . The compound according to  claim 1 , wherein one of R 7a  and R 7b  is hydrogen and the other is benzyl or hydroxybenzyl.  
   
   
       9 . The compound according to  claim 1 , wherein R 8  is benzyloxycarbonyl.  
   
   
       10 . The compound according to  claim 1 , wherein one of R 9a  and R 9b  is hydrogen and the other is benzyloxycarbonyl.  
   
   
       11 . The compound according to  claim 1 , wherein L is NH 2 .  
   
   
       12 . The compound according to  claim 1 , represented by the structure of any of formulas II-X.  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       13 . The compound according to  claim 12 , represented by the structure of formula II.  
   
   
       14 . The compound according to  claim 12 , represented by the structure of formula III.  
   
   
       15 . The compound according to  claim 12 , represented by the structure of formula IV.  
   
   
       16 . The compound according to  claim 12 , represented by the structure of formula V.  
   
   
       17 . The compound according to  claim 12 , represented by the structure of formula VI.  
   
   
       18 . The compound according to  claim 12 , represented by the structure of formula VII.  
   
   
       19 . The compound according to  claim 12 , represented by the structure of formula VIII.  
   
   
       20 . The compound according to  claim 12 , represented by the structure of formula IX.  
   
   
       21 . The compound according to  claim 12 , represented by the structure of formula X.  
   
   
       22 . The compound according to  claim 1 , wherein said compound comprises at least one pharmacophore potentially associated with a biological activity.  
   
   
       23 . The compound according to  claim 22 , wherein said biological activity is mediated by a cellular component, wherein said cellular component is a protein, a nucleic acid, or a combination thereof.  
   
   
       24 . The compound according to  claim 23 , wherein said biological activity is proliferation, differentiation, phenotype alteration, uptake, secretion, metabolism, gene expression, protein expression, or any combination thereof.  
   
   
       25 . A combinatorial library comprising a plurality of compounds represented by the structure of formula I:  
     
       
         
         
             
             
         
       
     
     wherein 
 A, B and D are independently of each other CH 2 , C═O or a bond;  
 X and Y are independently of each other O, S, C═O, S═O, SO 2 , CR 3a R 3b , NR 4  or C═S, or X and Y together form a group represented by the formula:  
                     
 R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a  and R 4b  are independently of each other hydrogen or a linear or branched chain alkyl;  
 m and n are independently of each other an integer of 1-6;  
 Z and Q are independently of each other  
                     
 R 5a , R 5b , R 6a , R 6b , R 7a , R 7b , R 8 , R 9a , and R 9b  are independently of each other hydrogen, a linear or branched chain alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, acyl, carboxyalkyl, carboxyaryl, benzyl, hydroxybenzyl, benzyloxycarbonyl, a side chain of a natural or unnatural amino acid or a peptide;  
 L is hydrogen, OR 10 , or NHR 11  wherein R 10  and R 11  are independently of each other hydrogen, a linear or branched chain alkyl, a side chain of a natural or unnatural amino acid, a peptide or a solid support; and  
                     
 is a heterocyclic moiety containing one or more nitrogens;  
 or a pharmaceutically acceptable salt, hydrate or solvate thereof.  
 
   
   
       26 . The library according to  claim 25 , comprising at least one compound of formula I wherein A and D are a bond and B is C═O.  
   
   
       27 . The library according to  claim 25 , comprising at least one compound of formula I wherein A is a bond, B is CH 2  are C is C═O.  
   
   
       28 . The library according to  claim 25 , comprising a plurality of compounds represented by the structure of any of formulas II-X.  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       29 . The library according to  claim 25 , comprising a plurality of compounds represented by the structure of formula II.  
   
   
       30 . The library according to  claim 25 , comprising a plurality of compounds represented by the structure of formula III.  
   
   
       31 . The library according to  claim 25 , comprising a plurality of compounds represented by the structure of formula IV.  
   
   
       32 . The library according to  claim 25 , comprising a plurality of compounds represented by the structure of formula V.  
   
   
       33 . The library according to  claim 25 , comprising a plurality of compounds represented by the structure of formula VI.  
   
   
       34 . The library according to  claim 25 , comprising a plurality of compounds represented by the structure of formula VII.  
   
   
       35 . The library according to  claim 25 , comprising a plurality of compounds represented by the structure of formula VIII.  
   
   
       36 . The library according to  claim 25 , comprising a plurality of compounds represented by the structure of formula IX.  
   
   
       37 . The library according to  claim 25 , comprising a plurality of compounds represented by the structure of formula X.  
   
   
       38 . The library according to  claim 25 , wherein each member of the library differs from the other by the size of the ring, the chirality of the substituents on the ring, or by a combination thereof.  
   
   
       39 . The library according to  claim 38 , wherein each member of the library further differs from the other by the chemical nature of the ring, the substituents on the ring, the linkers connecting the substituents and the ring, the arrangement of the substituents on the ring, or any combination thereof.  
   
   
       40 . The library according to  claim 25 , wherein each member of the library comprises at least one pharmacophore potentially associated with a biological activity.  
   
   
       41 . The library according to  claim 40 , wherein said biological activity is mediated by a cellular component, wherein said cellular component is a protein, a nucleic acid, or a combination thereof.  
   
   
       42 . The library according to  claim 41 , wherein said biological activity is proliferation, differentiation, phenotype alteration, uptake, secretion, metabolism, gene expression, protein expression, or any combination thereof.  
   
   
       43 . A method of identifying a compound having a beneficial biological activity, said method comprising the steps of: 
 designing a combinatorial library comprising a plurality of heterocyclic compounds according to  claim 1 , wherein each member of the library comprises at least one pharmacophore potentially associated with said biological activity;    synthesizing a plurality of compounds from said combinatorial library; and    screening said compounds for candidates having said biological activity.    
   
   
       44 . The method according to  claim 43 , wherein each member of the library differs from the other by the size of the ring, the chirality of the substituents on the ring, or by a combination thereof.  
   
   
       45 . The method according to  claim 43 , wherein some members of the library differs from the others by the chemical nature of the ring, the substituents on the ring, the linkers connecting the substituents and the ring, the arrangement of the substituents on the ring, or any combination thereof  
   
   
       46 . The method according to  claim 43 , wherein said biological activity is achieved by modulation of a cellular component.  
   
   
       47 . The method of  claim 46 , wherein said pharmacophore is complementary to a domain in said cellular component which is associated with said biological activity.  
   
   
       48 . The method according to  claim 43 , wherein said designing step further comprises: 
 identifying a domain in a cellular component which is associated with said biological activity; and    virtually screening said combinatorial library for lead compounds having a pharmacophore complementary to said domain.    
   
   
       49 . The method according to  claim 48 , wherein said virtual screening step comprises virtual screening with a computer readable data storage material encoded with computer readable data comprising three-dimensional structural determinants defining said domain.  
   
   
       50 . The method according to  claim 49 , wherein said computer readable data storage material is further encoded with a computer program logic for controlling a processor, said computer program logic comprising a procedure that enables said processor to identify a member of said combinatorial library having a pharmacophore complementary to said domain.  
   
   
       51 . The method according to  claim 48 , wherein said cellular component is a protein, a nucleic acid or a combination thereof.  
   
   
       52 . The method according to  claim 43 , wherein said biological activity is proliferation, differentiation, phenotype alteration, uptake, secretion, metabolism, gene expression, protein expression, or any combination thereof.  
   
   
       53 . A computer program product for virtual screening of a combinatorial library of heterocyclic compounds according to  claim 1  for a compound having a beneficial biological activity, said computer program product comprising: 
 a computer readable data storage material encoded with computer readable data comprising three-dimensional structural determinants defining a domain in a cellular component which is associated with said biological activity; and p 1  a computer program logic for controlling a processor, said computer program logic comprising a procedure that enables said processor to identify a compound having a pharmacophore complementary to said domain.    
   
   
       54 . The computer program product according to  claim 53 , wherein said cellular component is a protein, a nucleic acid or a combination thereof.  
   
   
       55 . The computer program product according to  claim 53 , wherein said biological activity is proliferation, differentiation, phenotype alteration, uptake, secretion, metabolism, gene expression, protein expression, or any combination thereof.  
   
   
       56 . The computer program product according to  claim 53 , wherein each member of the library differs from the other by the size of the ring, the chirality of the substituents on the ring, or by a combination thereof.  
   
   
       57 . The computer program product according to  claim 53 , wherein each member of the library differs from the other by the chemical nature of the ring, the substituents on the ring, the linkers connecting the substituents and the ring, the arrangement of the substituents on the ring, or any combination thereof  
   
   
       58 . A system for identifying a compound having a beneficial biological, comprising: 
 an automated device for virtual screening of a combinatorial library of heterocyclic compounds according to  claim 1  for a compound having said beneficial biological activity; and    an experimental device for screening said compounds for candidates having said biological activity.    
   
   
       59 . The system according to  claim 58 , wherein said automated device comprises a computer program product comprising: 
 a computer readable data storage material encoded with computer readable data comprising three-dimensional structural determinants defining a domain in a cellular component which is associated with said biological activity; and    a computer program logic for controlling a processor, said computer program logic comprising a procedure that enables said processor to identify a compound having a pharmacophore complementary to said domain.    
   
   
       60 . The system according to  claim 59 , wherein said cellular component is a protein, a nucleic acid or a combination thereof. complementary to said domain.  
   
   
       61 . The system according to  claim 58 , wherein said biological activity is proliferation, differentiation, phenotype alteration, uptake, secretion, metabolism, gene expression, protein expression, or any combination thereof.  
   
   
       62 . The system according to  claim 58 , wherein some members of the library differ from the others by the size of the ring, the chirality of the substituents on the ring, or by a combination thereof.  
   
   
       63 . The system according to  claim 58 , wherein each member of the library differs from the other by at least one additional feature selected from: the chemical nature of the ring, the substituents on the ring, the linkers connecting the substituents and the ring, the arrangement of the substituents on the ring, or any combination thereof.  
   
   
       64 . The system according to  claim 58 , wherein said experimental device comprises 
 an apparatus for synthesizing said compounds; and    an apparatus for screening said compounds for candidates having said biological activity.    
   
   
       65 . A pharmaceutical composition comprising at least one compound according to  claim 1 , and a pharmaceutically acceptable carrier.  
   
   
       66 . The composition according to  claim 65 , for therapeutic use in the treatment of a disease, disorder or condition.  
   
   
       67 . The composition according to  claim 66 , wherein a therapeutic effect is achieved by modulation of a cellular component, wherein said cellular component is a protein, a nucleic acid or a combination thereof.  
   
   
       68 . The composition according to  claim 67 , wherein the modulation of said cellular component affects a biological activity selected from proliferation, differentiation, phenotype alteration, uptake, secretion, metabolism, gene expression, protein expression, or any combination thereof.  
   
   
       69 . A method for the treatment of a disease, condition or disorder in a subject in need thereof, comprising the step of administering to said subject a therapeutically effective amount of a compound according to  claim 1 .  
   
   
       70 . The method according to  claim 69 , wherein a therapeutic effect is achieved by modulation of a cellular component in said subject, wherein said cellular component, is a protein, a nucleic acid, or a combination thereof.  
   
   
       71 . The method according to  claim 70 , wherein the modulation of cellular component affects a biological activity selected from proliferation, differentiation, phenotype alteration, uptake, secretion, metabolism, gene expression, protein expression, or any combination thereof.  
   
   
       72 . A method of modulating a cellular component in a cell, comprising the step of contacting said cell with a compound according to  claim 1 , in an amount effective to modulate said cellular component, wherein said cellular component is a protein, a nucleic acid, or a combination thereof.  
   
   
       73 . The method according to  claim 72 , wherein the modulation of said cellular component affects a biological activity selected from proliferation, differentiation, phenotype alteration, uptake, secretion, metabolism, gene expression, protein expression, or any combination thereof.  
   
   
       74 . A combinatorial library comprising a plurality of heterocyclic compounds, wherein the ring size of the heterocyclic compounds is between 8 and 20 atoms, and members of the library differ from each other by at least one of: the size of the ring; and the chirality of the substituents on the ring; wherein the members of the libraries comprise at least one common pharmacophore.  
   
   
       75 . The library according to  claim 74  wherein the members of the library may differ from each other by at least one additional parameter selected from the chemical nature of the ring; the order of the substituents on the ring; the type of linker connecting the substituent to the ring.