Calcitonin gene-related peptide (CGRP) is a 37 amino acid neuropeptide widely expressed in the peripheral and central nervous system that has been implicated in the pathogenesis of migraine headache. Antagonism of the CGRP receptor has been clinically validated to provide effective migraine relief comparable to the triptans with an improved adverse event profile. In our efforts to develop structurally novel, low-dose successors to telcagepant, our first-generation clinical candidate, we investigated a series of trisubstituted benzene compounds that represent a novel chemotype for CGRP receptor antagonists. This series makes interactions with the CLR portion of the heterodimer not observed for other chemotypes by inducing a new pocket to form in this part of the receptor (determined by receptor mutagenesis, X-ray crystallography, and NMR). Prior to these efforts, notably, only a small number of structural classes have been disclosed against this target despite nearly two decades of searching by the community. Initial hit to lead efforts led to the identification of compounds that posseses good potency (CGRP cAMP IC50 &lt; 10 nM) and selectivity (AM1 and AMY3 cAMP IC50 &gt; 20 μM) but suboptimal pharmacokinetic properties (rat F = 0%). Optimization of this series resulted in compounds with further improved potency and selectivity and substantially improved rodent and NHP PK, ultimately leading to the identification of a compound, 1, with high affinity for the receptor (Ki = 0.028 nM), potent in vivo activity (rhesus CIDV EC50 = 2.1 nM), a low potential human dose, and good off-target selectivity (e.g. hERG IC50 = 20 μM).

Rapid identification and optimization of a novel CGRP receptor antagonist chemotype

254th National Meeting (2017)

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