title: Orally bioavailable, liver-selective stearoyl-CoA desaturase (SCD) inhibitors.
abstract: We discovered a structurally novel SCD (Delta9 desaturase) inhibitor 4a (CVT-11,563) that has 119 nM potency in a human cell-based (HEPG2) SCD assay and selectivity against Delta5 and Delta6 desaturases. This compound has 90% oral bioavailability (rat) and excellent plasma exposure (dAUC 935 ng h/mL). Additionally, 4a shows moderately selective liver distribution (three times vs plasma and adipose tissue) and relatively low brain penetration. In a five-day study (high sucrose diet, rat) compound 4a significantly reduced SCD activity as determined by GC analysis of fatty acid composition in plasma and liver. We describe the discovery of 4a from HTS hit 1 followed by scaffold replacement and SAR studies focused on DMPK properties.
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: Natalya I
authors.initials: NI
authors.lastname: Vasilevich
authors.forename: Eric Q
authors.initials: EQ
authors.lastname: Parkhill
authors.forename: Andrei I
authors.initials: AI
authors.lastname: Glushkov
authors.forename: Timur M
authors.initials: TM
authors.lastname: Zilbershtein
authors.forename: Elena I
authors.initials: EI
authors.lastname: Mayboroda
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Boze
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: Nancy
authors.initials: N
authors.lastname: Chu
authors.forename: Jia
authors.initials: J
authors.lastname: Hao
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: D000284:Administration, Oral; D000818:Animals; D001593:Benzyl Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D004040:Dietary Carbohydrates / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D001593:Benzyl Compounds; C541977:CVT-11,563; D004040:Dietary Carbohydrates; D004791:Enzyme Inhibitors; D011744:Pyrimidinones; D013230:Stearoyl-CoA Desaturase