Design and synthesis of novel, potent and selective hypoxanthine analogs as adenosine A1 receptor antagonists and their biological evaluation

Summon Koul; Vidya Ramdas; Dinesh A Barawkar; Yogesh B Waman; Neela Prasad; Santosh Kumar Madadi; Yogesh D Shejul; Rajesh Bonagiri; Sujay Basu; Suraj Menon; Srinivasa B Reddy; Sandhya Chaturvedi; Srinivas Rao Chennamaneni; Gaurav Bedse; Rhishikesh Thakare; Jayasagar Gundu; Sumit Chaudhary; Siddhartha De; Ashwinkumar V Meru; Venkata Palle; Anita Chugh; Kasim A Mookhtiar

doi:10.1016/j.bmc.2017.02.029

Design and synthesis of novel, potent and selective hypoxanthine analogs as adenosine A₁ receptor antagonists and their biological evaluation

Bioorg Med Chem. 2017 Mar 15;25(6):1963-1975. doi: 10.1016/j.bmc.2017.02.029. Epub 2017 Feb 16.

Authors

Summon Koul¹, Vidya Ramdas², Dinesh A Barawkar², Yogesh B Waman², Neela Prasad², Santosh Kumar Madadi², Yogesh D Shejul², Rajesh Bonagiri², Sujay Basu², Suraj Menon², Srinivasa B Reddy², Sandhya Chaturvedi², Srinivas Rao Chennamaneni², Gaurav Bedse², Rhishikesh Thakare², Jayasagar Gundu², Sumit Chaudhary², Siddhartha De², Ashwinkumar V Meru², Venkata Palle², Anita Chugh², Kasim A Mookhtiar²

Affiliations

¹ Drug Discovery Unit, Advinus Therapeutics Ltd., Hinjewadi, Pune 411 057, India. Electronic address: summon.koul@advinus.com.
² Drug Discovery Unit, Advinus Therapeutics Ltd., Hinjewadi, Pune 411 057, India.

PMID: 28238512
DOI: 10.1016/j.bmc.2017.02.029

Abstract

Multipronged approach was used to synthesize a library of diverse C-8 cyclopentyl hypoxanthine analogs from a common intermediate III. Several potent and selective compounds were identified and evaluated for pharmacokinetic (PK) properties in Wistar rats. One of the compounds 14 with acceptable PK parameters was selected for testing in in vivo primary acute diuresis model. The compound demonstrated significant diuretic activity in this model.

Keywords: Adenosine; BG-9928; Diuresis; Glomerular; Hypoxanthine; Rolofylline.

MeSH terms

Adenosine A1 Receptor Antagonists / chemical synthesis
Adenosine A1 Receptor Antagonists / chemistry*
Adenosine A1 Receptor Antagonists / pharmacokinetics
Adenosine A1 Receptor Antagonists / pharmacology*
Animals
Carbon-13 Magnetic Resonance Spectroscopy
Chromatography, Liquid
Drug Design
HEK293 Cells
Humans
Hypoxanthines / chemical synthesis
Hypoxanthines / chemistry*
Hypoxanthines / pharmacokinetics
Hypoxanthines / pharmacology*
Male
Mass Spectrometry
Proton Magnetic Resonance Spectroscopy
Radioligand Assay
Rats
Rats, Wistar

Substances

Adenosine A1 Receptor Antagonists
Hypoxanthines