Orally bioavailable, liver-selective stearoyl-CoA desaturase (SCD) inhibitors.
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.
Koltun
Dmitry O
DO
Department of Medicinal Chemistry, CV Therapeutics, Inc, Palo Alto, CA 94304, USA. dmitry.koltun@cvt.com
Vasilevich
Natalya I
NI
Parkhill
Eric Q
EQ
Glushkov
Andrei I
AI
Zilbershtein
Timur M
TM
Mayboroda
Elena I
EI
Boze
Melanie A
MA
Cole
Andrew G
AG
Henderson
Ian
I
Zautke
Nathan A
NA
Brunn
Sandra A
SA
Chu
Nancy
N
Hao
Jia
J
Mollova
Nevena
N
Leung
Kwan
K
Chisholm
Jeffrey W
JW
Zablocki
Jeff
J
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
D001593:Benzyl Compounds; C541977:CVT-11,563; D004040:Dietary Carbohydrates; D004791:Enzyme Inhibitors; D011744:Pyrimidinones; D013230:Stearoyl-CoA Desaturase