title: MK-8825: a potent and selective CGRP receptor antagonist with good oral activity in rats.
abstract: Rational modification of the clinically tested CGRP receptor antagonist MK-3207 (3) afforded an analogue with increased unbound fraction in rat plasma and enhanced aqueous solubility, 2-[(8R)-8-(3,5-difluorophenyl)-8-methyl-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]-N-[(6S)-2'-oxo-1',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridin]-3-yl]acetamide (MK-8825) (6). Compound 6 maintained similar affinity to 3 at the human and rat CGRP receptors but possessed significantly improved in vivo potency in a rat pharmacodynamic model. The overall profile of 6 indicates it should find utility as a rat tool to investigate effects of CGRP receptor blockade in vivo.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. ian_bell@merck.com
authors.forename: Ian M
authors.initials: IM
authors.lastname: Bell
authors.forename: Craig A
authors.initials: CA
authors.lastname: Stump
authors.forename: Steven N
authors.initials: SN
authors.lastname: Gallicchio
authors.forename: Donnette D
authors.initials: DD
authors.lastname: Staas
authors.forename: C Blair
authors.initials: CB
authors.lastname: Zartman
authors.forename: Eric L
authors.initials: EL
authors.lastname: Moore
authors.forename: Nova
authors.initials: N
authors.lastname: Sain
authors.forename: Mark
authors.initials: M
authors.lastname: Urban
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Bruno
authors.forename: Amy
authors.initials: A
authors.lastname: Calamari
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Kemmerer
authors.forename: Scott D
authors.initials: SD
authors.lastname: Mosser
authors.forename: Christine
authors.initials: C
authors.lastname: Fandozzi
authors.forename: Rebecca B
authors.initials: RB
authors.lastname: White
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Zrada
authors.forename: Harold G
authors.initials: HG
authors.lastname: Selnick
authors.forename: Samuel L
authors.initials: SL
authors.lastname: Graham
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Vacca
authors.forename: Stefanie A
authors.initials: SA
authors.lastname: Kane
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Salvatore
mesh_terms: D000284:Administration, Oral; D000700:Analgesics / Q000097:blood / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D001682:Biological Availability; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D004195:Disease Models, Animal; D004285:Dogs; D006801:Humans; D008253:Macaca mulatta; D051379:Mice; D008881:Migraine Disorders / Q000188:drug therapy*; D011725:Pyridines / Q000097:blood / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000378:metabolism; D013045:Species Specificity; D013141:Spiro Compounds / Q000097:blood / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D000700:Analgesics; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; C575097:MK-8825; D011725:Pyridines; D018015:Receptors, Calcitonin Gene-Related Peptide; D013141:Spiro Compounds