title: Discovery of novel SCD1 inhibitors: 5-alkyl-4,5-dihydro-3H-spiro[1,5-benzoxazepine-2,4'-piperidine] analogs.
abstract: Expansion of the 6-membered ring and subsequent fine-tuning of the newly obtained 7-membered spiropiperidine structure resulted in the discovery of a series of novel and potent SCD1 inhibitors. Preliminary SAR was explored by modifying an alkyl chain on the azepine nitrogen and resulted in the identification of a highly potent SCD1 inhibitor: 6-[5-(cyclopropylmethyl)-4,5-dihydro-1'H,3H-spiro[1,5-benzoxazepine-2,4'-piperidin]-1'-yl]-N-(2-hydroxy-2-pyridin-3-ylethyl)pyridazine-3-carboxamide (9). Compound 9 exhibited an IC(50) value of 0.01 μM against human SCD1.
authors.affiliation: Lead Discovery & Optimization Research Laboratories I, Daiichi Sankyo Co., Ltd.,1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. uto.yoshikazu.pw@daiichisankyo.co.jp
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Uto
authors.forename: Yuko
authors.initials: Y
authors.lastname: Ueno
authors.forename: Yohei
authors.initials: Y
authors.lastname: Kiyotsuka
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Miyazawa
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kurata
authors.forename: Tsuneaki
authors.initials: T
authors.lastname: Ogata
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Takagi
authors.forename: Satoko
authors.initials: S
authors.lastname: Wakimoto
authors.forename: Jun
authors.initials: J
authors.lastname: Ohsumi
mesh_terms: D000818:Animals; D055808:Drug Discovery; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D010880:Piperidines; D013141:Spiro Compounds; C523776:SCD1 protein, human; C490333:Scd1 protein, mouse; D013230:Stearoyl-CoA Desaturase