Design and synthesis of 3,5-diarylisoxazole derivatives as novel class of anti-hyperglycemic and lipid lowering agents

Atul Kumar; Ram Awatar Maurya; Siddharth Sharma; Pervez Ahmad; A B Singh; A K Tamrakar; Arvind K Srivastava

doi:10.1016/j.bmc.2009.05.033

Design and synthesis of 3,5-diarylisoxazole derivatives as novel class of anti-hyperglycemic and lipid lowering agents

Bioorg Med Chem. 2009 Jul 15;17(14):5285-92. doi: 10.1016/j.bmc.2009.05.033. Epub 2009 May 18.

Authors

Atul Kumar¹, Ram Awatar Maurya, Siddharth Sharma, Pervez Ahmad, A B Singh, A K Tamrakar, Arvind K Srivastava

Affiliation

¹ Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow 226001, India. [email protected]

PMID: 19500993
DOI: 10.1016/j.bmc.2009.05.033

Abstract

We have designed 1,3-disubstituted-5-membered heteroaromatic ring system as a common core motif from known anti-hyperglycemic agents. Designed compounds were synthesized and screened for in vivo anti-hyperglycemic activity in sucrose loaded model (SLM), sucrose-challenged streptozotocin-induced diabetic rat model (STZ-S) as well as db/db mice model. Some of the synthesized compounds showed promising in vivo anti-hyperglycemic as well as moderate lipid lowering activity. Synthesized Compounds were screened in various in vitro models of type-2 diabeties such as DPP-4, PTP1B and PPARgamma to know the mechanism of their anti-hyperglycemic action. None of the synthesized compounds showed DPP-4 inhibitory as well as PPARgamma activity. These compounds have shown promising PTP-1B inhibitory activity there by revealing that compounds exhibit anti-diabetic activity by PTP1B pathway.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Blood Glucose / analysis
Blood Glucose / metabolism
Cholesterol / analysis
Cholesterol / metabolism
Diabetes Mellitus, Experimental / drug therapy*
Diabetes Mellitus, Type 2 / drug therapy*
Dose-Response Relationship, Drug
Hypoglycemic Agents / chemical synthesis
Hypoglycemic Agents / chemistry*
Hypoglycemic Agents / pharmacology
Hypoglycemic Agents / therapeutic use*
Hypolipidemic Agents / chemical synthesis
Hypolipidemic Agents / chemistry*
Hypolipidemic Agents / pharmacology
Hypolipidemic Agents / therapeutic use*
Isoxazoles / chemical synthesis
Isoxazoles / chemistry*
Isoxazoles / pharmacology
Isoxazoles / therapeutic use*
Male
Mice
Mice, Inbred C57BL
PPAR gamma / metabolism
Protein Tyrosine Phosphatase, Non-Receptor Type 1 / metabolism
Rats
Rats, Sprague-Dawley
Rats, Wistar
Streptozocin
Sucrose / administration & dosage
Triglycerides / analysis
Triglycerides / metabolism

Substances

Blood Glucose
Hypoglycemic Agents
Hypolipidemic Agents
Isoxazoles
PPAR gamma
Triglycerides
Sucrose
Streptozocin
Cholesterol
Protein Tyrosine Phosphatase, Non-Receptor Type 1
Ptpn1 protein, mouse