Method of drug design
The invention provides a method of identifying biologically active compounds comprising: (a) designing a first library of compounds of formula (1) to scan molecular diversity wherein each compound of the library has at least two pharmacophoric groups R1 to R5 as defined below and wherein compound of the library has same number of pharmacophoric groups; (b) assaying the first library of compounds in one or more biological assay(s); and (c) designing a second library wherein each compound of the second library contains one or more additional pharmacophoric group with respect to the first library; such that the/each component of the first and second library is a compound of formula (1).
1. A method of identifying biologically active compounds comprising:
(a) designing a first library of compounds of formula 1 to scan molecular diversity wherein for each compound of the first library R 2 and one of R 1 , R 3 , R 4 , and R 5 as defined below are pharmacophoric groups and the remainder of R 1 , R 3 , R 4 , and R 5 are non-pharmacophoric groups;
(b) assessing the first library of compounds in one or more biological activity assay(s); and
(c) designing a second library wherein for each compound of the second library the substituents R 1 to R 5 comprise the two pharmacophoric groups identified in step (b) and a third pharmacophoric group, and wherein the remainder of R 1 , R 3 , R 4 , and R 5 are non-pharmacophoric groups,
such that the/each component of the first and second library is a compound of formula 1:
wherein
Z is sulphur, oxygen, NH, NR A or hydrogen, in the case where Z is hydrogen then R 1 is not present;
R A is selected from the set defined for R 1 , R 3 , R 4 , and R 5 , or wherein Z and R 1 together form a heterocycle;
X is oxygen or nitrogen;
R 2 is a pharmacophoric group independently selected from the group consisting of C 2 to C 20 alkyl, C 2 to C 20 acyl, wherein said acyl is not acetyl; C 2 to C 20 alkenyl, C 2 to C 20 alkynyl, C 2 to C 20 heteroalkyl, C 5 to C 20 aryl, C 5 to C 20 heteroaryl, C 5 to C 20 arylalkyl and C 5 to C 20 heteroarylalkyl, which is optionally substituted, and can be branched or linear, or wherein NH and R 2 combine to form a heterocycle;
R 1 , R 3 , R 4 , and R 5 are each independently selected from
(i) non-pharmacophoric groups consisting of H, methyl and acetyl, and
(ii) pharmacophoric groups independently selected from the group consisting of C 2 to C 20 alkyl, C 2 to C 20 acyl, wherein said acyl is not acetyl; C 2 to C 20 alkenyl, C 2 to C 20 alkynyl, C 2 to C 20 heteroalkyl; C 5 to C 20 aryl, C 5 to C 20 heteroaryl, C 5 to C 20 arylalkyl and C 5 to C 20 heteroarylalkyl, which is optionally substituted, and can be branched or linear, or wherein X and the corresponding R moiety, R 3 to R 5 respectively, combine to form a heterocycle, and
wherein the optional substituent of each of R 2 and, when present as a pharmacophoric group R 1 , R 3 , R 4 , and R 5 , are selected from the group consisting of OH, NO, NO 2 , NH 2 , N 3 , halogen, CF 3 , CHF 2 , CH 2 F, nitrile, alkoxy, aryloxy, amidine, guanidiniums, carboxylic acid, carboxylic acid ester, aryl, cycloalkyl, heteroalkyl, heteroaryl, aminoalkyl, aminodialkyl, aminotrialkyl, aminoacyl, carbonyl, imine, sulfate, sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate, hydroxamic acid, heteroaryloxy, aminoaryl, aminoheteroaryl, thioalkyl, thioaryl and thioheteroaryl.
2. The method according to claim 1 , wherein Z is sulphur or oxygen.
3. The method according to claim 1 , wherein at least one of the pharmacophoric groups is selected from the group consisting of aryl, arylalkyl, heteroaryl, heteroarylalkyl and acyl.
4. The method according to claim 1 , wherein the/each component of each of the libraries is a compound selected from a compound of formula 2 or formula 3 or formula 4:
5. The method according to claim 1 , wherein the/each compound of the first library is of the gluco- or galacto-configuration.
6. The method according to claim 4 , wherein the/each compound of the second library is of the gluco- or galacto- or allo-configuration.
7. The method according to claim 6 , wherein the/each compound of the second library is of the gluco-configuration.
8. The method according to claim 6 , wherein the/each compound of the second library is of the allo-configuration.
9. The method according to claim 6 , wherein the/each compound of the second library is of the galacto-configuration.
10. The method according to claim 1 , wherein the biological assays involve peptide ligand class of GPCRs.
11. The method according to claim 1 , wherein NH and R 2 combine to form a heterocycle.
12. The method according to claim 11 , wherein the heterocycle is heteroaryl.
13. The method according to claim 11 , wherein the heterocycle is selected from group consisting of triazoles, benzimidazoles, benzimidazolone, benzimidazolothione, imidazole, hydantoine, thiohydantoine and purine.
14. The method according to claim 1 , wherein in the first library one pharmacophoric group comprises a positive charge and one pharmacophoric group is selected from the group consisting of aryl, heteroaryl, arylalkyl and heteroarylalkyl.
15. The method according to claim 1 , wherein the method further comprises the steps of
(d) assaying the second library of compounds in one or more biological assay(s); and
(e) designing a third library wherein for each compound of the third library the substituents R 1 to R 5 comprise the three active pharmacophoric groups identified in step (c) and a fourth pharmacophoric group, and wherein each component of the third library is a compound of formula 1.
16. The method according to claim 1 , wherein in each library when X is oxygen, R 1 , R 3 , R 4 and R 5 are each independently selected from
(i) non-pharmacophoric groups consisting of H, and methyl, and
(ii) pharmacophoric groups independently selected from the group consisting of C 2 to C 20 alkyl, C 2 to C 20 alkenyl, C 2 to C 20 alkynyl, C 2 to C 20 heteroalkyl, C 5 to C 20 aryl, C 5 to C 20 heteroaryl, C 5 to C 20 arylalkyl, and C 5 to C 20 heteroarylalkyl, which is optionally substituted, and can be branched or linear; and,
when X is nitrogen, R 1 , R 3 , R 4 and R 5 are each independently selected from
(i) a non-pharmacophoric group which is acetyl, and
(ii) pharmacophoric groups independently selected from the group consisting of C 2 to C 20 alkyl, C 2 to C 20 acyl wherein said acyl is not acetyl; C 2 to C 20 alkenyl, C 2 to C 20 alkynyl, C 2 to C 20 heteroalkyl, C 5 to C 20 aryl, C 5 to C 20 heteroaryl, C 5 to C 20 arylalkyl, and C 5 to C 20 heteroarylalkyl, which is optionally substituted, and can be branched or linear.
17. The method according to claim 16 , wherein Z is sulphur or oxygen.
18. The method according to claim 16 , wherein the/each component of each of the libraries is a compound selected from a compound of formula 2 or formula 3 or formula 4:
19. The method according to claim 17 , wherein the/each compound of the second library is of the gluco- or galacto- or allo-configuration.
20. The method according to claim 16 , wherein the/each compound of the first library is of the gluco- or galacto-configuration.
21. The method according to claim 16 , wherein in the first library one pharmacophoric group comprises a positive charge and one pharmacophoric group is selected from the group consisting of aryl, heteroaryl, arylalkyl and heteroarylalkyl.