The effect of 1,3-diaryl-[1H]-pyrazole-4-acetamides on glucose utilization in ob/ob mice

G R Bebernitz; G Argentieri; B Battle; C Brennan; B Balkan; B F Burkey; M Eckhardt; J Gao; P Kapa; R J Strohschein; H F Schuster; M Wilson; D D Xu

doi:10.1021/jm010032c

The effect of 1,3-diaryl-[1H]-pyrazole-4-acetamides on glucose utilization in ob/ob mice

J Med Chem. 2001 Aug 2;44(16):2601-11. doi: 10.1021/jm010032c.

Authors

G R Bebernitz¹, G Argentieri, B Battle, C Brennan, B Balkan, B F Burkey, M Eckhardt, J Gao, P Kapa, R J Strohschein, H F Schuster, M Wilson, D D Xu

Affiliation

¹ 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

PMID: 11472214
DOI: 10.1021/jm010032c

Abstract

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.

MeSH terms

Acetamides / chemical synthesis
Acetamides / chemistry
Acetamides / pharmacokinetics
Acetamides / pharmacology*
Adipose Tissue / cytology
Animals
Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
Anti-Inflammatory Agents, Non-Steroidal / chemistry
Anti-Inflammatory Agents, Non-Steroidal / pharmacokinetics
Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
Behavior, Animal / drug effects
Biological Availability
Blood Glucose / analysis
Cell Line
Diabetes Mellitus / blood
Diabetes Mellitus / drug therapy
Glucose / metabolism*
Hypoglycemic Agents / chemical synthesis
Hypoglycemic Agents / chemistry
Hypoglycemic Agents / pharmacokinetics
Hypoglycemic Agents / pharmacology*
Male
Mice
Mice, Inbred C57BL
Mice, Obese
Muscle, Skeletal / cytology
Pyrazoles / chemical synthesis
Pyrazoles / chemistry
Pyrazoles / pharmacokinetics
Pyrazoles / pharmacology*
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship

Substances

3-(1,1'-biphenyl)-4-yl-N,N-dimethyl-1-(3-(trifluoromethyl)phenyl)-1H-pyrazole-4-acetamide
Acetamides
Anti-Inflammatory Agents, Non-Steroidal
Blood Glucose
Hypoglycemic Agents
Pyrazoles
Glucose