The effect of 1,3-diaryl-[1H]-pyrazole-4-acetamides on glucose utilization in ob/ob mice.
This article provides evidence of a new class of compounds, 1,3-diaryl-[1H]-pyrazole-4-acetamides, initially identified from their ability to increase glucose transport in an adipocyte and muscle cell line and ultimately demonstrating dramatic glucose lowering in ob/ob mice, a diabetic animal model. The lead compound, 1, possessed some behavioral-like effects which were removed by structural variation during the course of this investigation. Specifically, 11g (R1 = meta-CF(3), Ar2 = 4'biphenyl, R3 = diethylamide) illustrated the potency of this series with ED(50) values for glucose lowering in ob/ob mice of 3.0 mg/kg/day. Concomitant with its effect on glucose lowering, 11g also caused a 50% reduction in insulin levels consistent with an agent that increases whole body insulin sensitivity. 11g showed favorable pharmacokinetic data with acceptable absorption, negligible metabolism, and good duration of action. 11g demonstrated no appreciable adipogenic effect through PPAR gamma agonism, a characteristic of the thiazolidinediones (TZD), and so represents a potentially new class of agents for the treatment of diabetes.
Bebernitz
G R
GR
Department of Medicinal Chemistry, Metabolic and Cardiovascular Diseases, Novartis Institute for Biomedical Research, Novartis Pharmaceuticals Corporation, 556 Morris Avenue, Summit, New Jersey 07901, USA. greg.bebernitz@pharma.novartis.com
Argentieri
G
G
Battle
B
B
Brennan
C
C
Balkan
B
B
Burkey
B F
BF
Eckhardt
M
M
Gao
J
J
Kapa
P
P
Strohschein
R J
RJ
Schuster
H F
HF
Wilson
M
M
Xu
D D
DD
D000081:Acetamides / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000273:Adipose Tissue / Q000166:cytology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001682:Biological Availability; D001786:Blood Glucose / Q000032:analysis; D002460:Cell Line; D003920:Diabetes Mellitus / Q000097:blood / Q000188:drug therapy; D005947:Glucose / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D018482:Muscle, Skeletal / Q000166:cytology; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
C432700:3-(1,1'-biphenyl)-4-yl-N,N-dimethyl-1-(3-(trifluoromethyl)phenyl)-1H-pyrazole-4-acetamide; D000081:Acetamides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D011720:Pyrazoles; D005947:Glucose