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. 2010 Jan 12;1(1):24-9.
doi: 10.1021/ml900016y. eCollection 2010 Apr 8.

Discovery of MK-3207: A Highly Potent, Orally Bioavailable CGRP Receptor Antagonist

Ian M Bell  1 , Steven N Gallicchio  1 , Michael R Wood  1 , Amy G Quigley  1 , Craig A Stump  1 , C Blair Zartman  1 , John F Fay  2 , Chi-Chung Li  3 , Joseph J Lynch  4 , Eric L Moore  5 , Scott D Mosser  2 , Thomayant Prueksaritanont  6 , Christopher P Regan  4 , Shane Roller  6 , Christopher A Salvatore  5 , Stefanie A Kane  5 , Joseph P Vacca  1 , Harold G Selnick  1
Affiliations

Discovery of MK-3207: A Highly Potent, Orally Bioavailable CGRP Receptor Antagonist

Ian M Bell et al. ACS Med Chem Lett. .

Abstract

Incorporation of polar functionality into a series of highly potent calcitonin gene-related peptide (CGRP) receptor antagonists was explored in an effort to improve pharmacokinetics. This strategy identified piperazinone analogues that possessed improved solubility at acidic pH and increased oral bioavailability in monkeys. Further optimization led to the discovery of the clinical candidate 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) (4), the most potent orally active CGRP receptor antagonist described to date.

Keywords: MK-3207; calcitonin gene-related peptide; pharmacokinetics; receptor antagonist.

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Figures

Chart 1
Chart 1. Selected CGRP Receptor Antagonists
Scheme 1
Scheme 1. Synthesis of Compound 4
Conditions: (a) Methyl 1-aminocyclopentanecarboxylate hydrochloride, Na3PO4, DMF. (b) Glycine ethyl ester hydrochloride, NaCNBH3, AcOH, MeOH, 50 °C. (c) Boc2O, DIEA, CH3CN, 60 °C. (d) Chiralcel OD, hexane:i-PrOH:Et2NH (60:40:0.1), (R)-enantiomer is second major peak. (e) LiOH, H2O, THF. (f) (R)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′-(1′H)-one, HATU, NMM, DMF. (g) HCl, EtOAc, 0 °C.
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