Design and synthesis of 3,5-diarylisoxazole derivatives as novel class of anti-hyperglycemic and lipid lowering agents.
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.
Kumar
Atul
A
Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow 226001, India. dratulsax@gmail.com
Maurya
Ram Awatar
RA
Sharma
Siddharth
S
Ahmad
Pervez
P
Singh
A B
AB
Tamrakar
A K
AK
Srivastava
Arvind K
AK
D000818:Animals; D001786:Blood Glucose / Q000032:analysis / Q000378:metabolism; D002784:Cholesterol / Q000032:analysis / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D000960:Hypolipidemic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047495:PPAR gamma / Q000378:metabolism; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013311:Streptozocin; D013395:Sucrose / Q000008:administration & dosage; D014280:Triglycerides / Q000032:analysis / Q000378:metabolism
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D007555:Isoxazoles; D047495:PPAR gamma; D014280:Triglycerides; D013395:Sucrose; D013311:Streptozocin; D002784:Cholesterol; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516609:Ptpn1 protein, mouse