The triptan drugs have been highly successful in the treatment of migraine, but adverse effects and low responder rates in some patients have provided the impetus to develop alternative therapies. Blockers of the calcitonin gene-related peptide (CGRP) receptor have emerged as promising alternatives to the triptans. Merck’s telcagepant has demonstrated efficacy comparable to the triptans in clinical trials and this novel mechanistic approach may offer relief to patients who do not respond well to triptan therapy. Concerns over raised liver enzymes (alanine transaminase, ALT) in prophylactic trials have hampered development of telcagepant but other molecules with different properties may address this issue.
Merck scientists have previously published papers describing the discovery of telcagepant (MK-0974) and a backup (MK-3207) and have now disclosed some additional work on related compounds in a recent letter. In attempting to improve upon telcagepant (MW=566) they sought to identify compounds with lower predicted clinical doses. They hoped to achieve this by replacing the caprolactam amide with heterocycles (to enhance solubility and lower plasma protein binding) and by identifying right-hand side replacements for the azabenzimidazolone group with improved metabolic stability.
To date, the optimisation of ligands for the GPCR receptor has proved to be non-trivial with most potent antagonists being of relatively high molecular weight. The data reported in this paper continues this theme and obtaining the right balance of properties in a limited chemical space proved to be very difficult. Overall, a spiro-azabenzoxazinone (see 30 above) on the right-hand side gave compounds with the best pharmacokinetic profiles and an appropriately substituted imidazole, as the caprolactam amide isostere, gave the best balance of potency, bioavailability, and hERG selectivity. This culminated in the discovery of MK-2918 which, whilst heavier (MW=580) and more lipophilic than telcagepant, had respectable preclinical properties and improved in vivo efficacy. In addition, increased stability in human microsomes relative to preclinical species and, interestingly, the high potency of it’s primary metabolite (the tertiary alcohol obtained by demethylation of the ether in 30) combined to give a lower anticipated clinical dose of MK-2918 relative to telcagepant. It’s not clear whether this compound has actually been progressed to the clinic or how straightforward developing a compound with this sort of profile would be. Hopefully some additional information relating to the progression of this molecule will be forthcoming in due course.