Discovery and Preclinical Evaluation of BMS-711939, an Oxybenzylglycine Based PPARα Selective Agonist.
BMS-711939 (3) is a potent and selective peroxisome proliferator-activated receptor (PPAR) α agonist, with an EC50 of 4 nM for human PPARα and >1000-fold selectivity vs human PPARγ (EC50 = 4.5 μM) and PPARδ (EC50 > 100 μM) in PPAR-GAL4 transactivation assays. Compound 3 also demonstrated excellent in vivo efficacy and safety profiles in preclinical studies and thus was chosen for further preclinical evaluation. The synthesis, structure-activity relationship (SAR) studies, and in vivo pharmacology of 3 in preclinical animal models as well as its ADME profile are described.
Research and Development, Bristol-Myers Squibb Company , 350 Carter Road, Hopewell, New Jersey 08540, United States.
Yan
Y
Shi
Research and Development, Bristol-Myers Squibb Company , 350 Carter Road, Hopewell, New Jersey 08540, United States.
Jun
J
Li
Research and Development, Bristol-Myers Squibb Company , 350 Carter Road, Hopewell, New Jersey 08540, United States.
Lawrence J
LJ
Kennedy
Research and Development, Bristol-Myers Squibb Company , 350 Carter Road, Hopewell, New Jersey 08540, United States.
Shiwei
S
Tao
Research and Development, Bristol-Myers Squibb Company , 350 Carter Road, Hopewell, New Jersey 08540, United States.
Andrés S
AS
Hernández
Research and Development, Bristol-Myers Squibb Company , 350 Carter Road, Hopewell, New Jersey 08540, United States.
Zhi
Z
Lai
Research and Development, Bristol-Myers Squibb Company , 350 Carter Road, Hopewell, New Jersey 08540, United States.
Sean
S
Chen
Research and Development, Bristol-Myers Squibb Company , 350 Carter Road, Hopewell, New Jersey 08540, United States.
Henry
H
Wong
Research and Development, Bristol-Myers Squibb Company , 350 Carter Road, Hopewell, New Jersey 08540, United States.
Juliang
J
Zhu
Research and Development, Bristol-Myers Squibb Company , 350 Carter Road, Hopewell, New Jersey 08540, United States.
Ashok
A
Trehan
Research and Development, Bristol-Myers Squibb Company , 350 Carter Road, Hopewell, New Jersey 08540, United States.
Ngiap-Kie
NK
Lim
Research and Development, Bristol-Myers Squibb Company , 350 Carter Road, Hopewell, New Jersey 08540, United States.
Huiping
H
Zhang
Research and Development, Bristol-Myers Squibb Company , 350 Carter Road, Hopewell, New Jersey 08540, United States.
Bang-Chi
BC
Chen
Research and Development, Bristol-Myers Squibb Company , 350 Carter Road, Hopewell, New Jersey 08540, United States.
Kenneth T
KT
Locke
Research and Development, Bristol-Myers Squibb Company , 350 Carter Road, Hopewell, New Jersey 08540, United States.
Kevin M
KM
O'Malley
Research and Development, Bristol-Myers Squibb Company , 350 Carter Road, Hopewell, New Jersey 08540, United States.
Litao
L
Zhang
Research and Development, Bristol-Myers Squibb Company , 350 Carter Road, Hopewell, New Jersey 08540, United States.
Rai Ajit
RA
Srivastava
Research and Development, Bristol-Myers Squibb Company , 350 Carter Road, Hopewell, New Jersey 08540, United States.
Bowman
B
Miao
Research and Development, Bristol-Myers Squibb Company , 350 Carter Road, Hopewell, New Jersey 08540, United States.
Daniel S
DS
Meyers
Research and Development, Bristol-Myers Squibb Company , 350 Carter Road, Hopewell, New Jersey 08540, United States.
Hossain
H
Monshizadegan
Research and Development, Bristol-Myers Squibb Company , 350 Carter Road, Hopewell, New Jersey 08540, United States.
Debra
D
Search
Research and Development, Bristol-Myers Squibb Company , 350 Carter Road, Hopewell, New Jersey 08540, United States.
Denise
D
Grimm
Research and Development, Bristol-Myers Squibb Company , 350 Carter Road, Hopewell, New Jersey 08540, United States.
Rongan
R
Zhang
Research and Development, Bristol-Myers Squibb Company , 350 Carter Road, Hopewell, New Jersey 08540, United States.
Thomas
T
Harrity
Research and Development, Bristol-Myers Squibb Company , 350 Carter Road, Hopewell, New Jersey 08540, United States.
Lori K
LK
Kunselman
Research and Development, Bristol-Myers Squibb Company , 350 Carter Road, Hopewell, New Jersey 08540, United States.
Michael
M
Cap
Research and Development, Bristol-Myers Squibb Company , 350 Carter Road, Hopewell, New Jersey 08540, United States.
Jodi
J
Muckelbauer
Research and Development, Bristol-Myers Squibb Company , 350 Carter Road, Hopewell, New Jersey 08540, United States.
Chiehying
C
Chang
Research and Development, Bristol-Myers Squibb Company , 350 Carter Road, Hopewell, New Jersey 08540, United States.
Stanley R
SR
Krystek
Research and Development, Bristol-Myers Squibb Company , 350 Carter Road, Hopewell, New Jersey 08540, United States.
Yi-Xin
YX
Li
Research and Development, Bristol-Myers Squibb Company , 350 Carter Road, Hopewell, New Jersey 08540, United States.
Vinayak
V
Hosagrahara
Research and Development, Bristol-Myers Squibb Company , 350 Carter Road, Hopewell, New Jersey 08540, United States.
Lisa
L
Zhang
Research and Development, Bristol-Myers Squibb Company , 350 Carter Road, Hopewell, New Jersey 08540, United States.
Pathanjali
P
Kadiyala
Research and Development, Bristol-Myers Squibb Company , 350 Carter Road, Hopewell, New Jersey 08540, United States.
Carrie
C
Xu
Research and Development, Bristol-Myers Squibb Company , 350 Carter Road, Hopewell, New Jersey 08540, United States.
Michael A
MA
Blanar
Research and Development, Bristol-Myers Squibb Company , 350 Carter Road, Hopewell, New Jersey 08540, United States.
Robert
R
Zahler
Research and Development, Bristol-Myers Squibb Company , 350 Carter Road, Hopewell, New Jersey 08540, United States.
Ranjan
R
Mukherjee
Research and Development, Bristol-Myers Squibb Company , 350 Carter Road, Hopewell, New Jersey 08540, United States.
Peter T W
PT
Cheng
Research and Development, Bristol-Myers Squibb Company , 350 Carter Road, Hopewell, New Jersey 08540, United States.
Joseph A
JA
Tino
Peroxisome proliferator-activated receptor (PPAR) α selective agonist; high fat fed hamster model; human ApoA1 transgenic mice; pharmacokinetics