title: Synthesis and evaluation of novel stearoyl-CoA desaturase 1 inhibitors: 1'-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-3,4-dihydrospiro[chromene-2,4'-piperidine] analogs.
abstract: In continuation of our investigation on novel stearoyl-CoA desaturase (SCD) 1 inhibitors, we have already reported on the structural modification of the benzoylpiperidines that led to a series of novel and highly potent spiropiperidine-based SCD1 inhibitors. In this report, we would like to extend the scope of our previous investigation and disclose details of the synthesis, SAR, ADME, PK, and pharmacological evaluation of the spiropiperidines with high potency for SCD1 inhibition. Our current efforts have culminated in the identification of 5-fluoro-1'-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-3,4-dihydrospiro[chromene-2,4'-piperidine] (10e), which demonstrated a very strong potency for liver SCD1 inhibition (ID(50)=0.6 mg/kg). This highly efficacious inhibition is presumed to be the result of a combination of strong enzymatic inhibitory activity (IC(50) (mouse)=2 nM) and good oral bioavailability (F >95%). Pharmacological evaluation of 10e has demonstrated potent, dose-dependent reduction of the plasma desaturation index in C57BL/6J mice on a high carbohydrate diet after a 7-day oral administration (q.d.). In addition, it did not cause any noticeable skin abnormalities up to the highest dose (10 mg/kg).
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: Makiko
authors.initials: M
authors.lastname: Yamada
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Deguchi
authors.forename: Masahiro
authors.initials: M
authors.lastname: Konishi
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; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008810:Mice, Inbred C57BL; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D011725:Pyridines; D013230:Stearoyl-CoA Desaturase