Potent, orally bioavailable, liver-selective stearoyl-CoA desaturase (SCD) inhibitors.
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%).
Koltun
Dmitry O
DO
Department of Medicinal Chemistry, Gilead Sciences, Inc., 3172 Porter Dr., Palo Alto, CA 94304, USA. dmitry.koltun@gilead.com
Zilbershtein
Timur M
TM
Migulin
Vasily A
VA
Vasilevich
Natalya I
NI
Parkhill
Eric Q
EQ
Glushkov
Andrei I
AI
McGregor
Malcolm J
MJ
Brunn
Sandra A
SA
Chu
Nancy
N
Hao
Jia
J
Mollova
Nevena
N
Leung
Kwan
K
Chisholm
Jeffrey W
JW
Zablocki
Jeff
J
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
D000081:Acetamides; D005227:Fatty Acids; D014280:Triglycerides; D013395:Sucrose; D013230:Stearoyl-CoA Desaturase