title: Discovery of liver-targeted inhibitors of stearoyl-CoA desaturase (SCD1).
abstract: Inhibitors based on a benzo-fused spirocyclic oxazepine scaffold were discovered for stearoyl-coenzyme A (CoA) desaturase 1 (SCD1) and subsequently optimized to potent compounds with favorable pharmacokinetic profiles and in vivo efficacy in reducing the desaturation index in a mouse model. Initial optimization revealed potency preferences for the oxazepine core and benzylic positions, while substituents on the piperidine portions were more tolerant and allowed for tuning of potency and PK properties. After preparation and testing of a range of functional groups on the piperidine nitrogen, three classes of analogs were identified with single digit nanomolar potency: glycine amides, heterocycle-linked amides, and thiazoles. Responding to concerns about target localization and potential mechanism-based side effects, an initial effort was also made to improve liver concentration in an available rat PK model. An advanced compound 17m with a 5-carboxy-2-thiazole substructure appended to the spirocyclic piperidine scaffold was developed which satisfied the in vitro and in vivo requirements for more detailed studies.
authors.affiliation: Merck Research Laboratories, 320 Bent Street, Cambridge, MA 02141, USA. yongqi.deng@merck.com
authors.forename: Yongqi
authors.initials: Y
authors.lastname: Deng
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Yang
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Shipps
authors.forename: Sie-Mun
authors.initials: SM
authors.lastname: Lo
authors.forename: Robert
authors.initials: R
authors.lastname: West
authors.forename: Joyce
authors.initials: J
authors.lastname: Hwa
authors.forename: Shuqin
authors.initials: S
authors.lastname: Zheng
authors.forename: Constance
authors.initials: C
authors.lastname: Farley
authors.forename: Jean
authors.initials: J
authors.lastname: Lachowicz
authors.forename: Margaret
authors.initials: M
authors.lastname: van Heek
authors.forename: Alan S
authors.initials: AS
authors.lastname: Bass
authors.forename: Dinesh P
authors.initials: DP
authors.lastname: Sinha
authors.forename: Craig R
authors.initials: CR
authors.lastname: Mahon
authors.forename: Mark E
authors.initials: ME
authors.lastname: Cartwright
mesh_terms: D000818:Animals; D003500:Cyclization; D003989:Dibenzoxazepines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D016503:Drug Delivery Systems; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008099:Liver / Q000201:enzymology*; D051379:Mice; D023421:Models, Animal; D015394:Molecular Structure; D051381:Rats; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors*
chemical_list: D003989:Dibenzoxazepines; D004791:Enzyme Inhibitors; D013141:Spiro Compounds; D013230:Stearoyl-CoA Desaturase