Design, synthesis and biological evaluation of novel aminomethyl-piperidones based DPP-IV inhibitors

Pradip Jadav; Rajesh Bahekar; Shailesh R Shah; Dipam Patel; Amit Joharapurkar; Mukul Jain; Kalapatapu V V M Sairam; Praveen Kumar Singh

doi:10.1016/j.bmcl.2014.03.009

Design, synthesis and biological evaluation of novel aminomethyl-piperidones based DPP-IV inhibitors

Bioorg Med Chem Lett. 2014 Apr 15;24(8):1918-22. doi: 10.1016/j.bmcl.2014.03.009. Epub 2014 Mar 12.

Authors

Pradip Jadav¹, Rajesh Bahekar², Shailesh R Shah³, Dipam Patel⁴, Amit Joharapurkar⁴, Mukul Jain⁴, Kalapatapu V V M Sairam⁴, Praveen Kumar Singh⁴

Affiliations

¹ Zydus Research Centre, Sarkhej-Bavla N.H. 8A Moraiya, Ahmedabad 382210, India; Department of Chemistry, Faculty of Science, M.S. University of Baroda, Vadodara 390002, India. Electronic address: [email protected].
² Zydus Research Centre, Sarkhej-Bavla N.H. 8A Moraiya, Ahmedabad 382210, India. Electronic address: [email protected].
³ Department of Chemistry, Faculty of Science, M.S. University of Baroda, Vadodara 390002, India. Electronic address: [email protected].
⁴ Zydus Research Centre, Sarkhej-Bavla N.H. 8A Moraiya, Ahmedabad 382210, India.

PMID: 24675378
DOI: 10.1016/j.bmcl.2014.03.009

Abstract

A series of novel aminomethyl-piperidones were designed and evaluated as potential DPP-IV inhibitors. Optimized analogue 12v ((4S,5S)-5-(aminomethyl)-1-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)-4-(2,5-difluorophenyl)piperidin-2-one) showed excellent in vitro potency and selectivity for DPP-IV over other serine proteases. The lead compound 12v showed potent and long acting antihyperglycemic effects (in vivo), along with improved pharmacokinetic profile.

Keywords: Aminomethyl-piperidones; Antidiabetic; DPP-IV inhibitors; Long-acting; Selective.

MeSH terms

Animals
Catalytic Domain
Dipeptidyl-Peptidase IV Inhibitors / chemical synthesis
Dipeptidyl-Peptidase IV Inhibitors / chemistry
Dipeptidyl-Peptidase IV Inhibitors / pharmacology
Drug Design*
Enzyme Activation / drug effects*
Hypoglycemic Agents / chemical synthesis
Hypoglycemic Agents / chemistry
Hypoglycemic Agents / pharmacology
Inhibitory Concentration 50
Male
Mice
Mice, Inbred C57BL
Models, Molecular
Molecular Structure
Piperidones / chemical synthesis*
Piperidones / chemistry
Piperidones / pharmacology*
Pyrazines / chemistry
Pyrazines / pharmacology
Sitagliptin Phosphate
Triazoles / chemistry
Triazoles / pharmacology

Substances

Dipeptidyl-Peptidase IV Inhibitors
Hypoglycemic Agents
Piperidones
Pyrazines
Triazoles
Sitagliptin Phosphate