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

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 0-oxo-1,1 0 ,2 0 ,3-tetrahydrospiro[indene-2,3 0-pyrrolo[2,3-b]pyridin]-5-yl]acetamide (MK-3207) (4), the most potent orally active CGRP receptor antagonist described to date.

CGRP receptor antagonists: an expanding drug class for acute migraine?

“…Telcagepant demonstrated a better pharmacokinetic profile, demonstrating at different doses both a good oral bioavailability and efficacy [67]. Compounds synthesized later were based on spiroindane template and led to MK-3207 [68], the second orally bioavailable CGRP-R antagonist. The utilization of the azabenzoxazinone spiropiperidine achieved the selection of MK-2918 [69], a preclinical candidate for the treatment of acute migraine.…”

Calcitonin gene-related peptide receptor antagonists for migraine

“…It had a t ½ of 1.6 h, reflected in the plasma concentrationdependent inhibition of capsaicin-induced vasodilatation [61]. Recently Merck reported several more compounds (including MK-3207) with higher affinity, in vitro and in vivo potency, bioavailability, and considerable structural diversity [62][63][64][65]. MK-3207 had also a slower off-rate of 59 min (t ½ ) compared with 1.3 min for telcagepant [66].…”

In Vivo Quantification of Calcitonin Gene-Related Peptide Receptor Occupancy by Telcagepant in Rhesus Monkey and Human Brain Using the Positron Emission Tomography Tracer [11C]MK-4232

“…19,29,3-tetrahydrospiro[indene-2,39-pyrrolo[2,3-b]pyridin]-5-yl]acetamide), CGRPA2, and N-desmethyl CGRPA2 were prepared at Merck Research Laboratories (West Point, PA) according to published methods (Paone et al, 2007;Bell et al, 2010Bell et al, , 2013. Radiochemical procedures were performed remotely in a lead hot cell using a modified 233XL liquid handler (Gilson, Inc., Middleton, WI) (Hostetler et al, 2001).…”