title: Discovery of a potent, orally available dual CysLT₁ and CysLT₂ antagonist with dicarboxylic acid.
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=13nM, 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, ClogP: >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.
authors: Medicinal Chemistry Research Laboratories, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan. Electronic address: itadani@ono.co.jp.
authors: Satoshi
authors: S
authors: Itadani
authors: Medicinal Chemistry Research Laboratories, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
authors: Shinya
authors: S
authors: Takahashi
authors: Medicinal Chemistry Research Laboratories, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
authors: Masaki
authors: M
authors: Ima
authors: Medicinal Chemistry Research Laboratories, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
authors: Tetsuya
authors: T
authors: Sekiguchi
authors: Medicinal Chemistry Research Laboratories, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
authors: Yoshiyuki
authors: Y
authors: Aratani
authors: Medicinal Chemistry Research Laboratories, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
authors: Hiromu
authors: H
authors: Egashira
authors: Exploratory Pharmaceutics Group Pharmaceutical Technology Laboratories, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
authors: Naoya
authors: N
authors: Matsumura
authors: Department of Biology & Pharmacology, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
authors: Atsuto
authors: A
authors: Inoue
authors: Department of Biology & Pharmacology, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
authors: Yasuo
authors: Y
authors: Yonetomi
authors: Department of Biology & Pharmacology, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
authors: Manabu
authors: M
authors: Fujita
authors: Medicinal Chemistry Research Laboratories, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
authors: Yoshisuke
authors: Y
authors: Nakayama
authors: Medicinal Chemistry Research Laboratories, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
authors: Jun
authors: J
authors: Takeuchi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D016466:CHO Cells; D018938:Caco-2 Cells; D003412:Cricetulus; D003998:Dicarboxylic Acids / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D057809:HEK293 Cells; D006801:Humans; D020024:Leukotriene Antagonists / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D018077:Receptors, Leukotriene / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D003998:Dicarboxylic Acids; D020024:Leukotriene Antagonists; D018077:Receptors, Leukotriene; C412375:cysteinyl leukotriene receptor 2; C083169:leukotriene D4 receptor
keywords: CysLT(1); CysLT(2); Dicarboxylic acid; Dual antagonist; HBDs; Pharmacokinetics