Synthesis, SAR and docking studies of substituted aryl phenylthiazolyl phenylcarboxamide as potential protein tyrosine phosphatase 1B (PTP1B) inhibitors

Kanika Varshney; Amit K Gupta; Arun Rawat; Rohit Srivastava; Akansha Mishra; Mridula Saxena; Arvind K Srivastava; Sudha Jain; Anil K Saxena

doi:10.1111/cbdd.13515

Synthesis, SAR and docking studies of substituted aryl phenylthiazolyl phenylcarboxamide as potential protein tyrosine phosphatase 1B (PTP1B) inhibitors

Chem Biol Drug Des. 2019 Jul;94(1):1378-1389. doi: 10.1111/cbdd.13515. Epub 2019 Jun 5.

Authors

Kanika Varshney^{1

2}, Amit K Gupta³, Arun Rawat⁴, Rohit Srivastava⁴, Akansha Mishra⁴, Mridula Saxena⁵, Arvind K Srivastava⁴, Sudha Jain², Anil K Saxena¹

Affiliations

¹ Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow, India.
² Department of Chemistry, Lucknow University, Lucknow, India.
³ Department of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas.
⁴ Biochemistry Division, Central Drug Research Institute, Lucknow, India.
⁵ Department of Chemistry, Amity University, Lucknow, India.

PMID: 30903642
DOI: 10.1111/cbdd.13515

Abstract

In our continued effort to discover novel PTP1B inhibitor with improved in vivo activity, we attempted to optimize our previously discovered lead compound by replacing the sulfonyl group with benzoyl group to yield compound II. Additional structural modifications were performed on compound II to yield a series of 24 aryl phenylthiazolyl phenylcarboxamides as potential PTP1B inhibitors. Of the 24 tested, 6 compounds showed good PTP1B inhibitory activity while compound 38 as the most promising one. The plausible PTP1B-binding site interaction of compound 38 showed favourable binding similar to known PTP1B binders and suggests its selectivity towards PTP1B. Compound 38 also showed promising antihyperglycaemic, antidyslipidaemic and insulin resistant reversal activities in vivo in STZ model and db/db mice model. Altogether, the compound 38 presents an excellent candidate for future PTP1B targeted drug discovery.

Keywords: PTP1B; Type 2 diabetes; aryl thiazolyl phenyl benzamide; docking.

Publication types

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

MeSH terms

Amides / chemistry*
Amides / metabolism
Amides / therapeutic use
Animals
Binding Sites
Blood Glucose / analysis
Catalytic Domain
Diabetes Mellitus, Experimental / chemically induced
Diabetes Mellitus, Experimental / drug therapy
Diabetes Mellitus, Experimental / pathology
Drug Design
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / metabolism
Enzyme Inhibitors / therapeutic use
Glucose Tolerance Test
Humans
Hypoglycemic Agents / chemical synthesis*
Hypoglycemic Agents / metabolism
Hypoglycemic Agents / therapeutic use
Hypolipidemic Agents / chemistry
Hypolipidemic Agents / metabolism
Hypolipidemic Agents / therapeutic use
Male
Mice
Mice, Inbred C57BL
Mice, Obese
Molecular Docking Simulation*
Protein Tyrosine Phosphatase, Non-Receptor Type 1 / antagonists & inhibitors*
Protein Tyrosine Phosphatase, Non-Receptor Type 1 / metabolism
Structure-Activity Relationship

Substances

Amides
Blood Glucose
Enzyme Inhibitors
Hypoglycemic Agents
Hypolipidemic Agents
Protein Tyrosine Phosphatase, Non-Receptor Type 1