title: Pharmacological properties of MK-3207, a potent and orally active calcitonin gene-related peptide receptor antagonist.
abstract: Calcitonin gene-related peptide (CGRP) has long been hypothesized to play a key role in migraine pathophysiology, and the advent of small-molecule antagonists has clearly demonstrated a clinical link between blocking the CGRP receptor and migraine efficacy. 2-[(8R)-8-(3,5-Difluorophenyl)-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]-N-[(2R)-2'-oxo-1,1',2',3-tetrahydrospiro[indene-2,3'-pyrrolo[2,3-b]pyridin]-5-yl]acetamide (MK-3207) represents the third CGRP receptor antagonist to display clinical efficacy in migraine trials. Here, we report the pharmacological characterization of MK-3207, a potent and orally bioavailable CGRP receptor antagonist. In vitro, MK-3207 is a potent antagonist of the human and rhesus monkey CGRP receptors (K(i) = 0.024 nM). In common with other CGRP receptor antagonists, MK-3207 displays lower affinity for CGRP receptors from other species, including canine and rodent. As a consequence of species selectivity, the in vivo potency was assessed in a rhesus monkey pharmacodynamic assay measuring capsaicin-induced changes in forearm dermal blood flow via laser Doppler imaging. MK-3207 produced a concentration-dependent inhibition of dermal vasodilation, with plasma concentrations of 0.8 and 7 nM required to block 50 and 90% of the blood flow increase, respectively. The tritiated analog [3H]MK-3207 was used to study the binding characteristics on the human CGRP receptor. [3H]MK-3207 displayed reversible and saturable binding (K(D) = 0.06 nM), and the off-rate was determined to be 0.012 min(-1), with a t(1/2) value of 59 min. In vitro autoradiography studies on rhesus monkey brain slices identified the highest level of binding in the cerebellum, brainstem, and meninges. Finally, as an index of central nervous system penetrability, the in vivo cerebrospinal fluid/plasma ratio was determined to be 2 to 3% in cisterna magna-ported rhesus monkeys.
authors.affiliation: Merck Research Laboratories, WP26A-2000, West Point, PA 19486, USA. christopher_salvatore@merck.com
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Salvatore
authors.forename: Eric L
authors.initials: EL
authors.lastname: Moore
authors.forename: Amy
authors.initials: A
authors.lastname: Calamari
authors.forename: Jacquelynn J
authors.initials: JJ
authors.lastname: Cook
authors.forename: Maria S
authors.initials: MS
authors.lastname: Michener
authors.forename: Stacey
authors.initials: S
authors.lastname: O'Malley
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Miller
authors.forename: Cyrille
authors.initials: C
authors.lastname: Sur
authors.forename: David L
authors.initials: DL
authors.lastname: Williams
authors.forename: Zhizhen
authors.initials: Z
authors.lastname: Zeng
authors.forename: Andrew
authors.initials: A
authors.lastname: Danziger
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Lynch
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Regan
authors.forename: John F
authors.initials: JF
authors.lastname: Fay
authors.forename: Yui S
authors.initials: YS
authors.lastname: Tang
authors.forename: Chi-Chung
authors.initials: CC
authors.lastname: Li
authors.forename: Nicole T
authors.initials: NT
authors.lastname: Pudvah
authors.forename: Rebecca B
authors.initials: RB
authors.lastname: White
authors.forename: Ian M
authors.initials: IM
authors.lastname: Bell
authors.forename: Steven N
authors.initials: SN
authors.lastname: Gallicchio
authors.forename: Samuel L
authors.initials: SL
authors.lastname: Graham
authors.forename: Harold G
authors.initials: HG
authors.lastname: Selnick
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Vacca
authors.forename: Stefanie A
authors.initials: SA
authors.lastname: Kane
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D001345:Autoradiography; D001667:Binding, Competitive; D001692:Biological Transport; D001921:Brain / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000097:blood / Q000134:cerebrospinal fluid / Q000494:pharmacology*; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002460:Cell Line; D002522:Chlorocebus aethiops; D005260:Female; D006801:Humans; D007700:Kinetics; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D011869:Radioligand Assay; D058265:Receptors, Adrenomedullin; D018003:Receptors, Calcitonin / Q000378:metabolism; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000502:physiology; D058287:Receptors, Islet Amyloid Polypeptide; D018000:Receptors, Peptide / Q000378:metabolism; D013141:Spiro Compounds / Q000097:blood / Q000134:cerebrospinal fluid / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects
chemical_list: C548781:2-(8-(3,5-difluorophenyl)-10-oxo-6,9-diazaspiro(4.5)dec-9-yl)-N-(2'-oxo-1,1',2',3-tetrahydrospiro(indene-2,3'-pyrrolo(2,3-b)pyridin)-5-yl)acetamide; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D019086:Bridged Bicyclo Compounds, Heterocyclic; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D058265:Receptors, Adrenomedullin; D018003:Receptors, Calcitonin; D018015:Receptors, Calcitonin Gene-Related Peptide; D058287:Receptors, Islet Amyloid Polypeptide; D018000:Receptors, Peptide; D013141:Spiro Compounds