Identification of a novel RAMP-independent CGRP receptor antagonist

C Blair Zartman; Ian M Bell; Steven N Gallicchio; Samuel L Graham; Stefanie A Kane; John J Mallee; Ruth Z Rutledge; Christopher A Salvatore; Joseph P Vacca; Theresa M Williams

doi:10.1016/j.bmcl.2011.09.056

Identification of a novel RAMP-independent CGRP receptor antagonist

Bioorg Med Chem Lett. 2011 Nov 15;21(22):6705-8. doi: 10.1016/j.bmcl.2011.09.056. Epub 2011 Sep 21.

Authors

C Blair Zartman¹, Ian M Bell, Steven N Gallicchio, Samuel L Graham, Stefanie A Kane, John J Mallee, Ruth Z Rutledge, Christopher A Salvatore, Joseph P Vacca, Theresa M Williams

Affiliation

¹ Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. blair_zartman@merck.com

PMID: 21982500
DOI: 10.1016/j.bmcl.2011.09.056

Abstract

Identification of an HIV integrase inhibitor with micromolar affinity for the CGRP receptor led to the discovery of a series of structurally novel CGRP receptor antagonists. Optimization of this series produced compound 16, a low-molecular weight CGRP receptor antagonist with good pharmacokinetic properties in both rat and dog. In contrast to other nonpeptide antagonists, the activity of 16 was affected by the presence of divalent cations and showed evidence of an alternative, RAMP-independent CGRP receptor binding site.

MeSH terms

Animals
Calcitonin Gene-Related Peptide Receptor Antagonists*
Cell Line
Dogs
HIV / enzymology
HIV Integrase Inhibitors / chemistry*
HIV Integrase Inhibitors / pharmacokinetics
HIV Integrase Inhibitors / pharmacology*
Humans
Protein Binding
Pyridines / chemistry*
Pyridines / pharmacokinetics
Pyridines / pharmacology*
Rats
Receptor Activity-Modifying Proteins / metabolism*
Receptors, Calcitonin Gene-Related Peptide / metabolism*

Substances

Calcitonin Gene-Related Peptide Receptor Antagonists
HIV Integrase Inhibitors
Pyridines
Receptor Activity-Modifying Proteins
Receptors, Calcitonin Gene-Related Peptide
hydroxypyridines