title: Synthesis, biological evaluation, and metabolic stability of acrylamide derivatives as novel CCR3 antagonists.
abstract: Our laboratory has identified several acrylamide derivatives with potent CCR3 inhibitory activity. In the present study, we evaluated the in vitro metabolic stability (CL(int); mL/min/kg) of these compounds in human liver microsomes (HLMs), and assessed the relationship between their structures and CL(int) values. Among the compounds identified, N-{(3R)-1-[(6-fluoro-2-naphthyl)methyl]pyrrolidin-3-yl}-2-[1-(2-hydroxybenzoyl)piperidin-4-ylidene]acetamide (30j) was found to be a potent inhibitor (IC(50)=8.4nM) with a high metabolic stability against HLMs.
authors.affiliation: Astellas Pharma Inc., Miyukigaoka, Tsukuba-shi, Ibaraki, Japan. ippei.sato@jp.astellas.com
authors.forename: Ippei
authors.initials: I
authors.lastname: Sato
authors.forename: Koichiro
authors.initials: K
authors.lastname: Morihira
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Inami
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Kubota
authors.forename: Tatsuaki
authors.initials: T
authors.lastname: Morokata
authors.forename: Keiko
authors.initials: K
authors.lastname: Suzuki
authors.forename: Kazuki
authors.initials: K
authors.lastname: Ohno
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Iura
authors.forename: Aiko
authors.initials: A
authors.lastname: Nitta
authors.forename: Takayuki
authors.initials: T
authors.lastname: Imaoka
authors.forename: Toshiya
authors.initials: T
authors.lastname: Takahashi
authors.forename: Makoto
authors.initials: M
authors.lastname: Takeuchi
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Ohta
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Tsukamoto
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000178:Acrylamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D018926:Anti-Allergic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D000882:Haplorhini; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D054397:Receptors, CCR3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013816:Thermodynamics
chemical_list: D000081:Acetamides; D000178:Acrylamides; D018926:Anti-Allergic Agents; C544483:N-((3R)-1-((6-fluoro-2-naphthyl)methyl)pyrrolidin-3-yl)-2-(1-(2-hydroxybenzoyl)piperidin-4-ylidene)acetamide; D009281:Naphthalenes; D010880:Piperidines; D020033:Protein Isoforms; D054397:Receptors, CCR3