Synthesis, biological evaluation, and metabolic stability of acrylamide derivatives as novel CCR3 antagonists.
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.
Sato
Ippei
I
Astellas Pharma Inc., Miyukigaoka, Tsukuba-shi, Ibaraki, Japan. ippei.sato@jp.astellas.com
Morihira
Koichiro
K
Inami
Hiroshi
H
Kubota
Hirokazu
H
Morokata
Tatsuaki
T
Suzuki
Keiko
K
Ohno
Kazuki
K
Iura
Yosuke
Y
Nitta
Aiko
A
Imaoka
Takayuki
T
Takahashi
Toshiya
T
Takeuchi
Makoto
M
Ohta
Mitsuaki
M
Tsukamoto
Shin-ichi
S
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
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