Novel, potent, selective, and metabolically stable stearoyl-CoA desaturase (SCD) inhibitors.
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.
Koltun
Dmitry O
DO
Department of Medicinal Chemistry, CV Therapeutics, Inc., Palo Alto, CA 94304, USA. dmitry.koltun@cvt.com
Parkhill
Eric Q
EQ
Vasilevich
Natalya I
NI
Glushkov
Andrei I
AI
Zilbershtein
Timur M
TM
Ivanov
Alexei V
AV
Cole
Andrew G
AG
Henderson
Ian
I
Zautke
Nathan A
NA
Brunn
Sandra A
SA
Mollova
Nevena
N
Leung
Kwan
K
Chisholm
Jeffrey W
JW
Zablocki
Jeff
J
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
D004791:Enzyme Inhibitors; D011621:Pteridines; D011810:Quinoxalines; D013230:Stearoyl-CoA Desaturase