In vitro and in vivo profile of 5-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylic acid benzylmethyl carbamoylamide (dirlotapide), a novel potent MTP inhibitor for obesity.
The synthesis of a novel gut selective MTP inhibitor, 5-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylic acid benzylmethyl carbamoylamide (dirlotapide), and its in vitro and in vivo profile are described. Dirlotapide (3) demonstrated excellent potency against MTP enzyme in HepG2 cells and canine hepatocytes. This novel MTP inhibitor also showed excellent efficacy when tested in a canine food intake model.
Li
Jin
J
Pfizer Inc., Groton, CT 06340, USA. jin.li@pfizer.com
Bronk
Brian S
BS
Dirlam
John P
JP
Blize
Alan E
AE
Bertinato
Peter
P
Jaynes
Burton H
BH
Hickman
Anne
A
Miskell
Christine
C
Pillai
Usha A
UA
Tibbitts
Jay S
JS
Haven
Michelle L
ML
Kolosko
Nicole L
NL
Barry
Chris J
CJ
Manion
Tara B
TB
D000818:Animals; D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004285:Dogs; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D008968:Molecular Conformation; D009765:Obesity / Q000188:drug therapy*; D051381:Rats
D002219:Carbamates; D002264:Carboxylic Acids; D002352:Carrier Proteins; D007211:Indoles; C106092:microsomal triglyceride transfer protein; C521290:dirlotapide