Calcitonin gene-related peptide (CGRP) receptor antagonists: novel aspartates and succinates

Guanglin Luo; Ling Chen; Sokhom S Pin; Cen Xu; Charles M Conway; John E Macor; Gene M Dubowchik

doi:10.1016/j.bmcl.2012.02.066

Calcitonin gene-related peptide (CGRP) receptor antagonists: novel aspartates and succinates

Bioorg Med Chem Lett. 2012 Apr 15;22(8):2912-6. doi: 10.1016/j.bmcl.2012.02.066. Epub 2012 Mar 3.

Authors

Guanglin Luo¹, Ling Chen, Sokhom S Pin, Cen Xu, Charles M Conway, John E Macor, Gene M Dubowchik

Affiliation

¹ Molecular Sciences and Candidate Optimization, Neuroscience Discovery Biology, Bristol-Myers Squibb Research & Development, Wallingford, CT 06492, USA. [email protected]

PMID: 22429471
DOI: 10.1016/j.bmcl.2012.02.066

Abstract

Novel aspartate and succinate CGRP full antagonists were identified through core modification of a potent lead CGRP antagonist, BMS-694153. While aspartates were much less active and had a flat SAR, some of the succinates were very potent CGRP full antagonists and matched the potency of BMS-694153. The most potency resides in the S enantiomer as demonstrated through an asymmetric synthesis.

MeSH terms

Aspartic Acid / chemical synthesis*
Aspartic Acid / chemistry
Aspartic Acid / pharmacology
Calcitonin Gene-Related Peptide Receptor Antagonists*
Humans
Indazoles / chemistry
Indazoles / pharmacology
Inhibitory Concentration 50
Molecular Structure
Protein Binding / drug effects
Quinazolinones / chemistry
Quinazolinones / pharmacology
Stereoisomerism
Structure-Activity Relationship
Succinates / chemical synthesis*
Succinates / chemistry
Succinates / pharmacology

Substances

4-(8-fluoro-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidin-1-yl)propan-2-yl)piperidine-1-carboxamide
Calcitonin Gene-Related Peptide Receptor Antagonists
Indazoles
Quinazolinones
Succinates
Aspartic Acid