title: Melanin-Concentrating Hormone Receptor 1 Antagonists Lacking an Aliphatic Amine: Synthesis and Structure-Activity Relationships of Novel 1-(Imidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one Derivatives.
abstract: Aiming to discover melanin-concentrating hormone receptor 1 (MCHR1) antagonists with improved safety profiles, we hypothesized that the aliphatic amine employed in most antagonists reported to date could be removed if the bicyclic motif of the compound scaffold interacted with Asp123 and/or Tyr272 of MCHR1. We excluded aliphatic amines from our compound designs, with a cutoff value of pK(a) < 8, and explored aliphatic amine-free MCHR1 antagonists in a CNS-oriented chemical space limited by four descriptors (TPSA, ClogP, MW, and HBD count). Screening of novel bicyclic motifs with high intrinsic binding affinity for MCHR1 identified the imidazo[1,2-a]pyridine ring (represented in compounds 6a and 6b), and subsequent cyclization of the central aliphatic amide linkage led to the discovery of a potent, orally bioavailable MCHR1 antagonist 4-[(4-chlorobenzyl)oxy]-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one 10a. It exhibited low potential for hERG inhibition and phospholipidosis induction as well as sufficient brain concentration to exert antiobesity effects in diet-induced obese rats.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., Shonan Research Center , 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Igawa
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., Shonan Research Center , 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., Shonan Research Center , 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Kakegawa
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., Shonan Research Center , 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Asato
authors.initials: A
authors.lastname: Kina
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., Shonan Research Center , 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Ikoma
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., Shonan Research Center , 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Jumpei
authors.initials: J
authors.lastname: Aida
authors.affiliation: CMC Center, Takeda Pharmaceutical Co., Ltd. , 17-85, Jusohonmachi 2-Chome, Yodogawa-ku, Osaka 532-8686, Japan.
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Yasuma
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., Shonan Research Center , 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Yayoi
authors.initials: Y
authors.lastname: Kawata
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., Shonan Research Center , 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Shuntaro
authors.initials: S
authors.lastname: Ashina
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., Shonan Research Center , 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Syunsuke
authors.initials: S
authors.lastname: Yamamoto
authors.affiliation: TCG Lifesciences Ltd. , Block BN, Plot 7, Saltlake Electronics Complex, Sector V, Kolkata 700091, India.
authors.forename: Mrinalkanti
authors.initials: M
authors.lastname: Kundu
authors.affiliation: TCG Lifesciences Ltd. , Block BN, Plot 7, Saltlake Electronics Complex, Sector V, Kolkata 700091, India.
authors.forename: Uttam
authors.initials: U
authors.lastname: Khamrai
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., Shonan Research Center , 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Hirabayashi
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., Shonan Research Center , 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Masaharu
authors.initials: M
authors.lastname: Nakayama
authors.affiliation: CVM Marketing Japan Pharma Business Unit, Takeda Pharmaceutical Co., Ltd. 12-10, Nihonbashi 2-Chome, Chuo-ku, Tokyo 103-8686, Japan.
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Nagisa
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., Shonan Research Center , 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Shizuo
authors.initials: S
authors.lastname: Kasai
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., Shonan Research Center , 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Maekawa
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016466:CHO Cells; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008297:Male; D015394:Molecular Structure; D009765:Obesity / Q000188:drug therapy*; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors* / Q000172:deficiency; D013329:Structure-Activity Relationship
chemical_list: C000609013:4-((4-chlorobenzyl)oxy)-1-(2-cyclopropyl-3-methylimidazo(1,2-a)pyridin-6-yl)pyridin-2(1H)-one; D019440:Anti-Obesity Agents; D007093:Imidazoles; C103263:MCHR1 protein, human; C491208:MCHR1 protein, rat; C491209:Mchr1 protein, mouse; D011728:Pyridones; D017481:Receptors, Somatostatin