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.

Bireshwar Dasgupta ¹, Edward Kozlowski ², Daniel R Schroeder ³, John R Torrente ³, Cen Xu ³, Sokhom Pin ³, Charlie M Conway ³, Gene M Dubowchik ², John E Macor ², Vivekananda M Vrudhula ⁴

Affiliations

1 Molecular Sciences and Candidate Optimization, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, United States. Electronic address: Bireshwar.Dasgupta@bms.com.
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: Vivekananda.Vrudhula@bms.com.

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.

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