Roxana Yang

Structure optimization of a leukotriene D4 antagonist by combinatorial chemistry in solution

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.

A convergent synthesis of Ro24-5913, a novel leukotriene D4 antagonist

Abstract A new and convergent synthesis of the leukotriene D 4 antagonist Ro24-5913 (9) has been developed that can serve both for technical production and combinatorial strcture optimization. The synthesis of 6 , achieved in 90% yield, is described. The conversion of 6 to 9 has been disclosed previously.

(2,3)-(α-methylenepenams: Synthesis and in vitro activity

Abstract A series of α-methylene penicillins was synthesized and SAR were studied. The α-isomers were found to be chemically reactive and biologically active in contrast to the β-isomers. In addition, the α-isomers have broader spectrum of in vitro activity than the corresponding penicillins. Generally, the α-isomers are more active against gram-negative bacteria than the corresponding penicillins, but slightly weaker in potency towards gram-positive organisms.