title: Potent, orally bioavailable, liver-selective stearoyl-CoA desaturase (SCD) inhibitors.
abstract: Two structurally distinct series of SCD (Delta9 desaturase) inhibitors (1 and 2) have been previously reported by our group. In the present work, we merged the structural features of the two series. This led to the discovery of compound 5b (CVT-12,012) which is highly potent in a human cell-based (HEPG2) SCD assay (IC(50)=6nM). This compound has 78% oral bioavailability in rats and is preferentially distributed into liver (76 times vs plasma) with relatively low brain penetration. In a five-day study (sucrose fed rats) compound 5b significantly reduced SCD activity in a dose-dependent manner as determined by GC analysis of fatty acid composition in plasma and liver, and significantly reduced liver triglycerides versus the control group ( approximately 50%).
authors: Department of Medicinal Chemistry, Gilead Sciences, Inc., 3172 Porter Dr., Palo Alto, CA 94304, USA. dmitry.koltun@gilead.com
authors: Dmitry O
authors: DO
authors: Koltun
authors: Timur M
authors: TM
authors: Zilbershtein
authors: Vasily A
authors: VA
authors: Migulin
authors: Natalya I
authors: NI
authors: Vasilevich
authors: Eric Q
authors: EQ
authors: Parkhill
authors: Andrei I
authors: AI
authors: Glushkov
authors: Malcolm J
authors: MJ
authors: McGregor
authors: Sandra A
authors: SA
authors: Brunn
authors: Nancy
authors: N
authors: Chu
authors: Jia
authors: J
authors: Hao
authors: Nevena
authors: N
authors: Mollova
authors: Kwan
authors: K
authors: Leung
authors: Jeffrey W
authors: JW
authors: Chisholm
authors: Jeff
authors: J
authors: Zablocki
mesh_terms: D000081:Acetamides / Q000737:chemistry; D000284:Administration, Oral; D000818:Animals; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004305:Dose-Response Relationship, Drug; D005227:Fatty Acids / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D008861:Microsomes / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013395:Sucrose / Q000737:chemistry; D014280:Triglycerides / Q000737:chemistry
chemical_list: D000081:Acetamides; D005227:Fatty Acids; D014280:Triglycerides; D013395:Sucrose; D013230:Stearoyl-CoA Desaturase