Diphenylpyridylethanamine (DPPE) derivatives as cholesteryl ester transfer protein (CETP) inhibitors.
A series of diphenylpyridylethanamine (DPPE) derivatives was identified exhibiting potent CETP inhibition. Replacing the labile ester functionality in the initial lead 7 generated a series of amides and ureas. Further optimization of the DPPE series for potency resulted in the discovery of cyclopentylurea 15d, which demonstrated a reduction in cholesterol ester transfer activity (48% of predose level) in hCETP/apoB-100 dual transgenic mice. The PK profile of 15d was suboptimal, and further optimization of the N-terminus resulted in the discovery of amide 20 with an improved PK profile and robust efficacy in transgenic hCETP/apoB-100 mice and in hamsters. Compound 20 demonstrated no significant changes in either mean arterial blood pressure or heart rate in telemeterized rats despite sustained high exposures.
Department of Chemistry, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, USA. Lalgudi.Harikrishnan@bms.com
Lalgudi S
LS
Harikrishnan
Heather J
HJ
Finlay
Jennifer X
JX
Qiao
Muthoni G
MG
Kamau
Ji
J
Jiang
Tammy C
TC
Wang
James
J
Li
Christopher B
CB
Cooper
Michael A
MA
Poss
Leonard P
LP
Adam
David S
DS
Taylor
Alice Ye A
AY
Chen
Xiaohong
X
Yin
Paul G
PG
Sleph
Richard Z
RZ
Yang
Doree F
DF
Sitkoff
Michael A
MA
Galella
David S
DS
Nirschl
Katy
K
Van Kirk
Arthur V
AV
Miller
Christine S
CS
Huang
Ming
M
Chang
Xue-Qing
XQ
Chen
Mark E
ME
Salvati
Ruth R
RR
Wexler
R Michael
RM
Lawrence
D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D053299:Apolipoprotein B-100 / Q000037:antagonists & inhibitors / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003327:Coronary Disease / Q000188:drug therapy; D006224:Cricetinae; D055808:Drug Discovery; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D013267:Stilbenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
D000924:Anticholesteremic Agents; D053299:Apolipoprotein B-100; C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D011725:Pyridines; D013267:Stilbenes