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

[Display omitted] 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=25nM) showed excellent pharmacokineti...

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Veröffentlicht in:	Bioorganic & medicinal chemistry 2015-05, Vol.23 (9), p.2079-2097
Hauptverfasser:	Itadani, Satoshi, Takahashi, Shinya, Ima, Masaki, Sekiguchi, Tetsuya, Aratani, Yoshiyuki, Egashira, Hiromu, Matsumura, Naoya, Inoue, Atsuto, Yonetomi, Yasuo, Fujita, Manabu, Nakayama, Yoshisuke, Takeuchi, Jun
Format:	Artikel
Sprache:	eng
Schlagworte:	Administration, Oral Animals Biological Availability Caco-2 Cells CHO Cells Cricetulus CysLT1 CysLT2 Dicarboxylic acid Dicarboxylic Acids - administration & dosage Dicarboxylic Acids - chemistry Dicarboxylic Acids - pharmacology Dose-Response Relationship, Drug Drug Discovery Dual antagonist HBDs HEK293 Cells Humans Leukotriene Antagonists - administration & dosage Leukotriene Antagonists - chemistry Leukotriene Antagonists - pharmacology Molecular Structure Pharmacokinetics Receptors, Leukotriene - metabolism Structure-Activity Relationship
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Zusammenfassung:	[Display omitted] 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=25nM) 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:
ISSN:	0968-0896 1464-3391
DOI:	10.1016/j.bmc.2015.03.011