Invention of novel 3-aminopiperidin-2-ones as calcitonin gene-related peptide receptor antagonists.

A novel series of 3-amino-piperidin-2-one-based calcitonin gene-related peptide (CGRP) receptor antagonists was invented based upon the discovery of unexpected structure-activity observations. Initial exploration of the structure-activity relationships enabled the generation of a moderately potent lead structure (4). A series of modifications, including ring contraction and inversion of stereocenters, led to surprising improvements in CGRP receptor affinity. These studies identified compound 23, a structurally novel potent, orally bioavailable CGRP receptor antagonist.

Identification of second-generation P2X3 antagonists for treatment of pain.

A second-generation small molecule P2X3 receptor antagonist has been developed. The lead optimization strategy to address shortcomings of the first-generation preclinical lead compound is described herein. These studies were directed towards the identification and amelioration of preclinical hepatobiliary findings, reducing potential for drug-drug interactions, and decreasing the projected human dose of the first-generation lead.

Novel oxazolidinone calcitonin gene-related peptide (CGRP) receptor antagonists for the acute treatment of migraine.

In our efforts to develop CGRP receptor antagonists as backups to MK-3207, 2, we employed a scaffold hopping approach to identify a series of novel oxazolidinone-based compounds. The development of a structurally diverse, potent (20, cAMP+HS IC50=0.67 nM), and selective compound (hERG IC50=19 µM) with favorable rodent pharmacokinetics (F=100%, t1/2=7h) is described. Key to this development was identification of a 3-substituted spirotetrahydropyran ring that afforded a substantial gain in potency (10 to 35-fold).

Orally bioavailable imidazoazepanes as calcitonin gene-related peptide (CGRP) receptor antagonists: discovery of MK-2918.

In our ongoing efforts to develop CGRP receptor antagonists for the treatment of migraine, we aimed to improve upon telecagepant by targeting a compound with a lower projected clinical dose. Imidazoazepanes were identified as potent caprolactam replacements and SAR of the imidazole yielded the tertiary methyl ether as an optimal substituent for potency and hERG selectivity. Combination with the azabenzoxazinone spiropiperidine ultimately led to preclinical candidate 30 (MK-2918).

Imidazopyridine CB2 agonists: optimization of CB2/CB1 selectivity and implications for in vivo analgesic efficacy.

A new series of imidazopyridine CB2 agonists is described. Structural optimization improved CB2/CB1 selectivity in this series and conferred physical properties that facilitated high in vivo exposure, both centrally and peripherally. Administration of a highly selective CB2 agonist in a rat model of analgesia was ineffective despite substantial CNS exposure, while administration of a moderately selective CB2/CB1 agonist exhibited significant analgesic effects.

Optimization of azepanone calcitonin gene-related peptide (CGRP) receptor antagonists: development of novel spiropiperidines.

Several novel spiropiperidine-based CGRP receptor antagonists have been developed that maintain good potency and have reduced potential for metabolism.

Synthesis of the (3R,6S)-3-amino-6-(2,3-difluorophenyl)azepan-2-one of telcagepant (MK-0974), a calcitonin gene-related peptide receptor antagonist for the treatment of migraine headache.

Two novel routes have been developed to the (3 R,6 S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one 2 of the CGRP receptor antagonist clinical candidate telcagepant (MK-0974, 1). The first employs a ring-closing metathesis of the styrene 7 as the key reaction, while the second makes use of a highly diastereoselective Hayashi-Miyaura Rh-catalyzed arylboronic acid addition to nitroalkene 16. The latter route has been implemented to produce multigram quantities of telcagepant for extensive preclinical evaluation.