Discovery of a Potent, Orally Available Dual CysLT1 and CysLT2 Antagonist with Dicarboxylic Acid

Authors: Itadani S, Takahashi S, Ima M, Sekiguchi T, Aratani Y, Egashira H, Matsumura N, Inoue A, Yonetomi Y, Fujita M, Nakayama Y, Takeuchi J
Publication: Bioorg Med Chem
Keywords: CysLT1, CysLT2, dicarboxylic acid, dual antagonist, HBDs, pharmacokinetics
Software: ADMET Predictor®

Abstract

A potent, orally available dual CysLT1 and CysLT2 receptor antagonist with a dicarboxylic acid is described. 4-(3-(Carboxymethyl)-4-{(E)-2-[4-(4-phenoxybutoxy)phenyl]vinyl}-1H-indol-1-yl)butanoic acid (15: ONO–4310321, IC50: CysLT1 = 13 nM, CysLT2 = 25 nM) showed excellent pharmacokinetic profiles (%Frat = 100) compared with our previously reported compound 1 (%Frat = 1.5). In addition, we describe a new rule for dicarboxylic acid derivatives to show good oral bioavailability (%Frat ⩾ 40) in rats (HBDs: ⩽2, C log P: >6.5 and TPSA: <100). Especially, reduction of only one hydrogen-bond donor (HBDs) showed dramatically improved oral bioavailability. This small change of HBDs in dicarboxylic acid derivatives is generally a very effective modification.