N6-Cycloalkyl-2-substituted adenosine derivatives as selective, high affinity adenosine A1 receptor agonists

Elfatih Elzein; Rao Kalla; Xiaofen Li; Thao Perry; Tim Marquart; Mark Micklatcher; Yuan Li; Yuzhi Wu; Dewan Zeng; Jeff Zablocki

doi:10.1016/j.bmcl.2006.09.065

N6-Cycloalkyl-2-substituted adenosine derivatives as selective, high affinity adenosine A1 receptor agonists

Bioorg Med Chem Lett. 2007 Jan 1;17(1):161-6. doi: 10.1016/j.bmcl.2006.09.065. Epub 2006 Oct 11.

Authors

Elfatih Elzein¹, Rao Kalla, Xiaofen Li, Thao Perry, Tim Marquart, Mark Micklatcher, Yuan Li, Yuzhi Wu, Dewan Zeng, Jeff Zablocki

Affiliation

¹ Department of Bioorganic Chemistry, CV Therapeutics Inc., 3172 Porter Drive, Palo Alto, CA 94304, USA. elfatih.elzein@cvt.com

PMID: 17045477
DOI: 10.1016/j.bmcl.2006.09.065

Abstract

A series of new selective, high affinity A(1)-AdoR agonists is reported. Compound 23 that incorporated a carboxylic acid functionality in the 4-position of the pyrazole ring displayed K(iL) value of 1 nM for the A(1)-AdoR and >5000-fold selectivity over the A(3) and A(2A)-AdoRs. In addition, compound 19 that incorporated a carboxamide functionality in the 4-position of the pyrazole ring displayed subnanomolar affinity for the A(1)-AdoR (K(iL)=0.6 nM) and >600-fold selectivity over the A(3) and A(2A)-AdoRs.

MeSH terms

Adenosine / analogs & derivatives*
Adenosine / chemistry*
Adenosine / pharmacology
Adenosine A1 Receptor Agonists*
Anti-Arrhythmia Agents / chemistry*
Anti-Arrhythmia Agents / pharmacology
Humans
Hypolipidemic Agents / chemistry*
Hypolipidemic Agents / pharmacology
Molecular Structure
Pyrazoles / chemistry*
Pyrazoles / pharmacology

Substances

Adenosine A1 Receptor Agonists
Anti-Arrhythmia Agents
Hypolipidemic Agents
N-cyclopentyl-2-(4-carbamoylpyrazol-1-yl)adenosine
N-norbornyl-2-(4-carboxypyrazol-1-yl)adenosine
Pyrazoles
Adenosine