Design and synthesis of N-[(4-methoxyphenoxy)carbonyl]-N-[[4-[2-(5- methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]methyl]glycine [Muraglitazar/BMS-298585], a novel peroxisome proliferator-activated receptor alpha/gamma dual agonist with efficacious glucose and lipid-lowering activities.
Muraglitazar/BMS-298585 (2) has been identified as a non-thiazolidinedione PPAR alpha/gamma dual agonist that shows potent activity in vitro at human PPARalpha (EC(50) = 320 nM) and PPARgamma(EC(50) = 110 nM). Compound 2 shows excellent efficacy for lowering glucose, insulin, triglycerides, and free fatty acids in genetically obese, severely diabetic db/db mice and has a favorable ADME profile. Compound 2 is currently in clinical development for the treatment of type 2 diabetes and dyslipidemia.
Devasthale
Pratik V
PV
Metabolic Diseases Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-5400, USA. pratik.devasthale@bms.com
Chen
Sean
S
Jeon
Yoon
Y
Qu
Fucheng
F
Shao
Chunning
C
Wang
Wei
W
Zhang
Hao
H
Cap
Michael
M
Farrelly
Dennis
D
Golla
Rajasree
R
Grover
Gary
G
Harrity
Thomas
T
Ma
Zhengping
Z
Moore
Lisa
L
Ren
Jimmy
J
Seethala
Ramakrishna
R
Cheng
Lin
L
Sleph
Paul
P
Sun
Wei
W
Tieman
Aaron
A
Wetterau
John R
JR
Doweyko
Arthur
A
Chandrasena
Gamini
G
Chang
Shu Y
SY
Humphreys
W Griffith
WG
Sasseville
Vito G
VG
Biller
Scott A
SA
Ryono
Denis E
DE
Selan
Fred
F
Hariharan
Narayanan
N
Cheng
Peter T W
PT
D017667:Adipocytes / Q000166:cytology; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D005227:Fatty Acids / Q000097:blood; D005998:Glycine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006949:Hyperlipidemias / Q000188:drug therapy; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000960:Hypolipidemic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D007328:Insulin / Q000097:blood; D008297:Male; D051379:Mice; D008820:Mice, Obese; D010080:Oxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D047493:PPAR alpha / Q000819:agonists*; D047495:PPAR gamma / Q000819:agonists*; D015533:Transcriptional Activation; D014280:Triglycerides / Q000097:blood
D001786:Blood Glucose; D005227:Fatty Acids; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D007328:Insulin; D010080:Oxazoles; D047493:PPAR alpha; D047495:PPAR gamma; D014280:Triglycerides; D005998:Glycine; C500085:muraglitazar