Serendipitous oxidation product of BIBN4096BS: a potent CGRP receptor antagonist

Bireshwar Dasgupta; Edward Kozlowski; Daniel R Schroeder; John R Torrente; Cen Xu; Sokhom Pin; Charlie M Conway; Gene M Dubowchik; John E Macor; Vivekananda M Vrudhula

doi:10.1016/j.bmcl.2014.04.033

Serendipitous oxidation product of BIBN4096BS: a potent CGRP receptor antagonist

Bioorg Med Chem Lett. 2014 Jun 15;24(12):2744-8. doi: 10.1016/j.bmcl.2014.04.033. Epub 2014 Apr 18.

Affiliations

¹ Molecular Sciences and Candidate Optimization, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, United States. Electronic address: [email protected].
² Molecular Sciences and Candidate Optimization, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, United States.
³ Neuroscience Discovery Biology, Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, United States.
⁴ Molecular Sciences and Candidate Optimization, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, United States. Electronic address: [email protected].

PMID: 24794104
DOI: 10.1016/j.bmcl.2014.04.033

Abstract

An oxidation product (5) formed during the synthesis of BIBN-4096BS (1) was found to be a potent CGRP antagonist (IC50=0.11nM). While 5 was found to be ten-fold less potent than 1, another analog 8 with lower molecular weight containing the oxidized fragment demonstrated twenty-fold higher activity than its parent 7. Alternative conditions which preclude the formation of the oxidation product are described. The activities of 1, 5, 7 and 8 in functional cAMP assay are also discussed.

Keywords: Antagonists; BIBN4096BS; CGRP.

MeSH terms

Biological Assay
Calcitonin Gene-Related Peptide Receptor Antagonists*
Inhibitory Concentration 50
Molecular Structure
Oxidation-Reduction
Piperazines / chemical synthesis
Piperazines / chemistry*
Piperazines / pharmacology
Quinazolines / chemical synthesis
Quinazolines / chemistry*
Quinazolines / pharmacology

Substances

Calcitonin Gene-Related Peptide Receptor Antagonists
Piperazines
Quinazolines
olcegepant