title: Novel, potent, selective, and metabolically stable stearoyl-CoA desaturase (SCD) inhibitors.
abstract: We identified a series of structurally novel SCD (Delta9 desaturase) inhibitors via high-throughput screening and follow-up SAR studies. Modification of the central bicyclic scaffold has proven key to our potency optimization effort. The most potent analog (8g) had IC(50) value of 50 pM in a HEPG2 SCD assay and has been shown to be metabolically stable and selective against Delta5 and Delta6 desaturases.
authors.affiliation: Department of Medicinal Chemistry, CV Therapeutics, Inc., Palo Alto, CA 94304, USA. dmitry.koltun@cvt.com
authors.forename: Dmitry O
authors.initials: DO
authors.lastname: Koltun
authors.forename: Eric Q
authors.initials: EQ
authors.lastname: Parkhill
authors.forename: Natalya I
authors.initials: NI
authors.lastname: Vasilevich
authors.forename: Andrei I
authors.initials: AI
authors.lastname: Glushkov
authors.forename: Timur M
authors.initials: TM
authors.lastname: Zilbershtein
authors.forename: Alexei V
authors.initials: AV
authors.lastname: Ivanov
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Cole
authors.forename: Ian
authors.initials: I
authors.lastname: Henderson
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Zautke
authors.forename: Sandra A
authors.initials: SA
authors.lastname: Brunn
authors.forename: Nevena
authors.initials: N
authors.lastname: Mollova
authors.forename: Kwan
authors.initials: K
authors.lastname: Leung
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Chisholm
authors.forename: Jeff
authors.initials: J
authors.lastname: Zablocki
mesh_terms: D000818:Animals; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D008861:Microsomes / Q000378:metabolism; D011621:Pteridines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011810:Quinoxalines / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D011621:Pteridines; D011810:Quinoxalines; D013230:Stearoyl-CoA Desaturase