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: [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.
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