title: Structure optimization of a leukotriene D4 antagonist by combinatorial chemistry in solution.
abstract: Structure optimization of the leukotriene D4 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 LTD4-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, ic = {C1, C2, C3}, from which the preferred element C1 was selected. Incorporating this selection into the synthesis of the first reduced set gave the partition 7(10A B C1) whose assay revealed the set iB = {B1, B6} and hence the preferred B element B1. The second reduced set, 10(A B1 C1) incorporating the selected C1 and B1 moieties, revealed iA = {A1, A3, A4, A6, A7, A8, A9} In the resulting combinatiorial product iA x iB x iC, comprising 42 elements, A1 B1 C1 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.
authors.affiliation: Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA.
authors.forename: H
authors.initials: H
authors.lastname: Maehr
authors.forename: R
authors.initials: R
authors.lastname: Yang
mesh_terms: D000818:Animals; D018927:Anti-Asthmatic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D006168:Guinea Pigs; D017998:Leukotriene D4 / Q000037:antagonists & inhibitors*; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D012996:Solutions; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D018927:Anti-Asthmatic Agents; D012996:Solutions; D013844:Thiazoles; C071436:cinalukast; D017998:Leukotriene D4