Design, synthesis and biological evaluation of novel pyrazolo-pyrimidinones as DPP-IV inhibitors in diabetes

Sneha R Sagar; Jessica K Agarwal; Dhaivat H Pandya; Ranjeet Prasad Dash; Manish Nivsarkar; Kamala K Vasu

doi:10.1016/j.bmcl.2015.09.015

Design, synthesis and biological evaluation of novel pyrazolo-pyrimidinones as DPP-IV inhibitors in diabetes

Bioorg Med Chem Lett. 2015 Oct 15;25(20):4428-33. doi: 10.1016/j.bmcl.2015.09.015. Epub 2015 Sep 8.

Authors

Sneha R Sagar¹, Jessica K Agarwal², Dhaivat H Pandya³, Ranjeet Prasad Dash⁴, Manish Nivsarkar⁴, Kamala K Vasu⁵

Affiliations

¹ Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research-Ahmedabad, S. G. Highway, Thaltej, Ahmedabad 380054, Gujarat, India; Department of Medicinal Chemistry, B. V. Patel Pharmaceutical Education and Research Development (PERD) Centre, S. G. Highway, Thaltej, Ahmedabad 380054, Gujarat, India.
² Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research-Ahmedabad, S. G. Highway, Thaltej, Ahmedabad 380054, Gujarat, India.
³ Department of Medicinal Chemistry, B. V. Patel Pharmaceutical Education and Research Development (PERD) Centre, S. G. Highway, Thaltej, Ahmedabad 380054, Gujarat, India.
⁴ Department of Pharmacology and Toxicology, B. V. Patel Pharmaceutical Education and Research Development (PERD) Centre, S. G. Highway, Thaltej, Ahmedabad 380054, Gujarat, India.
⁵ Department of Medicinal Chemistry, B. V. Patel Pharmaceutical Education and Research Development (PERD) Centre, S. G. Highway, Thaltej, Ahmedabad 380054, Gujarat, India. Electronic address: kamalav@perdcentre.com.

PMID: 26372650
DOI: 10.1016/j.bmcl.2015.09.015

Abstract

We report the design, synthesis, biological activity and docking studies of series of novel pyrazolo[3,4-d]pyrimidinones as DPP-IV inhibitors in diabetes. Molecules were synthesized and evaluated for their DPP-IV inhibition activity. Compounds 5e, 5k, 5o and 6a were found to be potent inhibitors of DPP-IV enzyme. Amongst all the synthesized compounds, 6-methyl-5-(4-methylpyridin-2-yl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (5k) was found to be the most active based on in vitro DPP-IV studies and also exhibited promising in vivo blood glucose lowering activity in male Wistar rats.

Keywords: DPP-IV enzyme; Molecular docking; Pyrazolo-pyrimidinones.

MeSH terms

Animals
Blood Glucose / drug effects
Blood Glucose / metabolism
Diabetes Mellitus, Experimental / chemically induced
Diabetes Mellitus, Experimental / drug therapy*
Diabetes Mellitus, Experimental / metabolism
Dipeptidyl Peptidase 4 / metabolism*
Dose-Response Relationship, Drug
Drug Design*
Hyperglycemia / chemically induced
Hyperglycemia / drug therapy
Hyperglycemia / metabolism
Hypoglycemic Agents / chemical synthesis
Hypoglycemic Agents / chemistry
Hypoglycemic Agents / pharmacology*
Male
Models, Molecular
Molecular Structure
Pyrazoles / chemistry*
Pyrimidinones / chemical synthesis
Pyrimidinones / chemistry
Pyrimidinones / pharmacology*
Rats
Rats, Wistar
Structure-Activity Relationship

Substances

Blood Glucose
Hypoglycemic Agents
Pyrazoles
Pyrimidinones
pyrazole
DPP4 protein, rat
Dipeptidyl Peptidase 4