title: Discovery of trans-4-[1-[[2,5-Dichloro-4-(1-methyl-3-indolylcarboxamido)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid: an orally active, selective very late antigen-4 antagonist.
abstract: We have focused on optimization of the inadequate pharmacokinetic profile of trans-4-substituted cyclohexanecarboxylic acid 5, which is commonly observed in many small molecule very late antigen-4 (VLA-4) antagonists. We modified the lipophilic moiety in 5 and found that reducing the polar surface area of this moiety results in improvement of the PK profile. Consequently, our efforts have led to the discovery of trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxamido)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid (14e) with potent activity (IC(50) = 5.4 nM) and significantly improved bioavailability in rats, dogs, and monkeys (100%, 91%, 68%), which demonstrated excellent oral efficacy in murine and guinea pig models of asthma. Based on its overall profile, compound 14e was progressed into clinical trails. In a single ascending-dose phase I clinical study, compound 14e exhibited favorable oral exposure as expected and had no serious adverse events.
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd., Tokyo 134-8630, Japan. muro.fumihito.iy@daiichisankyo.co.jp
authors.forename: Fumihito
authors.initials: F
authors.lastname: Muro
authors.forename: Shin
authors.initials: S
authors.lastname: Iimura
authors.forename: Yuuichi
authors.initials: Y
authors.lastname: Sugimoto
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Yoneda
authors.forename: Jun
authors.initials: J
authors.lastname: Chiba
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Watanabe
authors.forename: Masaki
authors.initials: M
authors.lastname: Setoguchi
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Iigou
authors.forename: Keiko
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Atsushi
authors.initials: A
authors.lastname: Satoh
authors.forename: Gensuke
authors.initials: G
authors.lastname: Takayama
authors.forename: Tomoe
authors.initials: T
authors.lastname: Taira
authors.forename: Mika
authors.initials: M
authors.lastname: Yokoyama
authors.forename: Tohru
authors.initials: T
authors.lastname: Takashi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nakayama
authors.forename: Nobuo
authors.initials: N
authors.lastname: Machinaga
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003509:Cyclohexanecarboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000494:pharmacology; D004285:Dogs; D006168:Guinea Pigs; D000882:Haplorhini; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors*; D051379:Mice; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D003509:Cyclohexanecarboxylic Acids; D007211:Indoles; D039041:Integrin alpha4beta1; D011759:Pyrrolidines