A novel series of highly potent benzimidazole-based microsomal triglyceride transfer protein inhibitors.
A series of benzimidazole-based analogues of the potent MTP inhibitor BMS-201038 were discovered. Incorporation of an unsubstituted benzimidazole moiety in place of a piperidine group afforded potent inhibitors of MTP in vitro which were weakly active in vivo. Appropriate substitution on the benzimidazole ring, especially with small alkyl groups, led to dramatic increases in potency, both in a cellular assay of apoB secretion and especially in animal models of cholesterol lowering. The most potent in this series, 3g (BMS-212122), was significantly more potent than BMS-201038 in reducing plasma lipids (cholesterol, VLDL/LDL, TG) in both hamsters and cynomolgus monkeys.
Robl
J A
JA
The Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 5400, Princeton, New Jersey 08543-5400, USA. Jeffrey.Robl@bms.com
Sulsky
R
R
Sun
C Q
CQ
Simpkins
L M
LM
Wang
T
T
Dickson
J K
JK
Chen
Y
Y
Magnin
D R
DR
Taunk
P
P
Slusarchyk
W A
WA
Biller
S A
SA
Lan
S J
SJ
Connolly
F
F
Kunselman
L K
LK
Sabrah
T
T
Jamil
H
H
Gordon
D
D
Harrity
T W
TW
Wetterau
J R
JR
D000284:Administration, Oral; D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001055:Apolipoproteins B / Q000097:blood / Q000378:metabolism; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D002460:Cell Line; D002784:Cholesterol / Q000097:blood; D006224:Cricetinae; D005449:Fluorenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D000960:Hypolipidemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000097:blood; D008252:Macaca fascicularis; D008861:Microsomes / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014280:Triglycerides / Q000097:blood / Q000378:metabolism
C424429:9-(4-(2,5-dimethyl-4-(((4'-(trifluoromethyl)(1,1'-biphenyl)-2-yl)carbonyl)amino)-1H-benzimidazol-1-yl)butyl)-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide; D000924:Anticholesteremic Agents; D001055:Apolipoproteins B; D001562:Benzimidazoles; D002352:Carrier Proteins; D005449:Fluorenes; D000960:Hypolipidemic Agents; D008077:Lipoproteins, LDL; D014280:Triglycerides; C106092:microsomal triglyceride transfer protein; D002784:Cholesterol