title: Identification of a novel RAMP-independent CGRP receptor antagonist.
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.
authors: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. blair_zartman@merck.com
authors: C Blair
authors: CB
authors: Zartman
authors: Ian M
authors: IM
authors: Bell
authors: Steven N
authors: SN
authors: Gallicchio
authors: Samuel L
authors: SL
authors: Graham
authors: Stefanie A
authors: SA
authors: Kane
authors: John J
authors: JJ
authors: Mallee
authors: Ruth Z
authors: RZ
authors: Rutledge
authors: Christopher A
authors: CA
authors: Salvatore
authors: Joseph P
authors: JP
authors: Vacca
authors: Theresa M
authors: TM
authors: Williams
mesh_terms: D000818:Animals; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002460:Cell Line; D004285:Dogs; D006678:HIV / Q000201:enzymology; D019428:HIV Integrase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D011485:Protein Binding; D011725:Pyridines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D058261:Receptor Activity-Modifying Proteins / Q000378:metabolism*; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000378:metabolism*
chemical_list: D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D019428:HIV Integrase Inhibitors; D011725:Pyridines; D058261:Receptor Activity-Modifying Proteins; D018015:Receptors, Calcitonin Gene-Related Peptide; C014047:hydroxypyridines