title: Design, synthesis and identification of novel benzimidazole derivatives as highly potent NPY Y5 receptor antagonists with attractive in vitro ADME profiles.
abstract: Optimization of our HTS hit 1, mainly focused on modification at the C-2 position of the benzimidazole core, is described. Elimination of the flexible and metabolically labile -S-CH(2)- part and utilization of less lipophilic pyridone substructure led to identification of novel NPY Y5 receptor antagonists 6, which have low to sub-nanomolar Y5 receptor binding affinity with improved CYP450 inhibition profiles, good solubilities and high metabolic stabilities.
authors.affiliation: Medicinal Research Laboratories, Shionogi & Co., Ltd., 1-1, Futabacho 3-chome, Toyonaka, Osaka 561-0825, Japan. yuusuke.tamura@shionogi.co.jp
authors.forename: Yuusuke
authors.initials: Y
authors.lastname: Tamura
authors.forename: Naoki
authors.initials: N
authors.lastname: Omori
authors.forename: Naoki
authors.initials: N
authors.lastname: Kouyama
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nishiura
authors.forename: Kyouhei
authors.initials: K
authors.lastname: Hayashi
authors.forename: Kana
authors.initials: K
authors.lastname: Watanabe
authors.forename: Yukari
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Takeshi
authors.initials: T
authors.lastname: Chiba
authors.forename: Hideo
authors.initials: H
authors.lastname: Yukioka
authors.forename: Hiroki
authors.initials: H
authors.lastname: Sato
authors.forename: Takayuki
authors.initials: T
authors.lastname: Okuno
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D009765:Obesity / Q000188:drug therapy; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D001562:Benzimidazoles; D065607:Cytochrome P-450 Enzyme Inhibitors; D011728:Pyridones; D017476:Receptors, Neuropeptide Y; C100568:neuropeptide Y5 receptor; D003577:Cytochrome P-450 Enzyme System