Discovery of a potent, orally available dual CysLT1 and CysLT2 antagonist with dicarboxylic acid

A potent, orally available dual CysLT 1 and CysLT 2 receptor antagonist with a dicarboxylic acid is described. 4-(3-(Carboxymethyl)-4-{( E )-2-[4-(4-phenoxybutoxy)phenyl]vinyl}-1 H -indol-1-yl)butanoic acid ( 15 : ONO - 4310321 , IC 50 : CysLT 1  = 13 nM, CysLT 2  = 25 nM) showed excellent pharmacokinetic profiles (% F rat  = 100) compared with our previously reported compound 1 (% F rat  = 1.5). In addition, we describe a new rule for dicarboxylic acid derivatives to show good oral bioavailability (% F rat  ⩾ 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.