Structure optimization of a leukotriene D 4 antagonist by combinatorial chemistry in solution

• Published in: Bioorganic & medicinal chemistry Vol. 5; no. 3; pp. 493 - 496
• Main Authors: Maehr, Hubert, Yang, Roxana
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 01.03.1997
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/S0968-0896(96)00278-7

Structure optimization of the leukotriene D 4 antagonist Ro24–5913 was attempted by combinatorial chemistry. Three segments in its N-succinyl-3-(2-thiazolylethenyl)anilide skeleton, designated as A, B, and C coincided with the thiazolyl, aniline, and N-acyl moieties, respectively, and were selected for variations in a synthesis involving the sequences A + B → AB and AB + C → ABC to furnish the library ( 10A 7B 10C) containing 700 compounds. Lead candidates were identified by the LTD 4-induced muscle-contraction assay. Assays of the C-partition 10( 10A 7B C) of the set led to a subset of C elements associated with significant bioactivities, i c = {C 1, C 2, C 3}, from which the preferred element C 1 was selected. Incorporating this selection into the synthesis of the first reduced set gave the partition 7( 10A B C 1) whose assay revealed the set i B = {B 1, B 6} and hence the preferred B element B 1. The second reduced set, 10(A B 1 C 1) incorporating the selected C 1 and B 1 moieties, revealed i A = {A 1, A 3, A 4, A 6, A 7, A 8, A 9}. In the resulting combinatorial product i A × i B × i C, comprising 42 elements, A 1 B 1 C 1 appears on top of the list. Thus, 4-[[3-[2-[4-(2,2-dimethyl ethyl)cyclobutyl-2-thiazolyl]ethenyl] phenyl]amino]-2,2-diethyl-4-oxobutanoic acid (Ro24–5913) was confirmed as the structure with the highest bioactivity. Analogues obtained by replacement of the cyclobutyl group in Ro24–5913 with 4-fluorophenyl and t-butyl were the runners-up. Of these, the former exhibited bioactivity comparable to that of Ro24–5913. The optimum structural features were deduced by the introduction of molecular diversity at three sites followed by the evaluation of a library containing 700 compounds.