CVT-4325: a potent fatty acid oxidation inhibitor with favorable oral bioavailability.
New inhibitors of palmitoyl-CoA oxidation are based on the introduction of nitrogen heterocycles in the 'Western Portion' of the molecule. SAR studies led to the discovery of CVT-4325 (shown), a potent FOXi (IC50=380 nM rat mitochondria) with favorable PK properties (F=93%, t(1/2)=13.6h, dog).
Elzein
Elfatih
E
Department of Bioorganic Chemistry, CV Therapeutics, Inc., 3172 Porter Dr., Palo Alto, CA 94304, USA.
Ibrahim
Prabha
P
Koltun
Dmitry O
DO
Rehder
Ken
K
Shenk
Kevin D
KD
Marquart
Timothy A
TA
Jiang
Bob
B
Li
Xiaofen
X
Natero
Reina
R
Li
Yuan
Y
Nguyen
Marie
M
Kerwar
Suresh
S
Chu
Nancy
N
Soohoo
Daniel
D
Hao
Jia
J
Maydanik
Victoria Y
VY
Lustig
David A
DA
Zeng
Dewan
D
Leung
Kwan
K
Zablocki
Jeff A
JA
D000284:Administration, Oral; D000818:Animals; D000975:Antioxidants / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001682:Biological Availability; D004285:Dogs; D005227:Fatty Acids / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008968:Molecular Conformation; D010069:Oxadiazoles / Q000493:pharmacokinetics* / Q000494:pharmacology*; D010084:Oxidation-Reduction / Q000187:drug effects; D010171:Palmitoyl Coenzyme A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship
D000975:Antioxidants; D005227:Fatty Acids; D010069:Oxadiazoles; C499690:para-trifluoro-methyl-5-phenyl-1,2,4-oxadiazole; D010171:Palmitoyl Coenzyme A