Calcitonin gene-related peptide (CGRP) is a potent neuropeptide that plays a key role in the pathophysiology of migraine headache. CGRP levels in the cranial circulation are increased during a migraine attack, and CGRP itself has been shown to trigger migraine-like headache. The correlation between CGRP release and migraine headache points to the potential utility of CGRP receptor antagonists as novel therapeutics in the treatment of migraine. Indeed, clinical proof-of-concept in the acute treatment of migraine was demonstrated with an intravenous formulation of the CGRP receptor antagonist BIBN4096BS (olcegepant). Here we report on the pharmacological characterization of the first orally bioavailable CGRP receptor antagonist in clinical development, MK-MK-0974 is a potent antagonist of the human (K i ϭ 0.77 nM) and rhesus (K i ϭ 1.2 nM) CGRP receptors but displays Ͼ1500-fold lower affinity for the canine and rat receptors as determined via 125 I-human CGRP competition binding assays. A rhesus pharmacodynamic assay measuring capsaicin-induced changes in forearm dermal blood flow via laser Doppler imaging was utilized to determine the in vivo activity of CGRP receptor antagonism. MK-0974 produced a concentration-dependent inhibition of dermal vasodilation, generated by capsaicininduced release of endogenous CGRP, with plasma concentrations of 127 and 994 nM required to block 50 and 90% of the blood flow increase, respectively. In conclusion, MK-0974 is a highly potent, selective, and orally bioavailable CGRP receptor antagonist, which may be valuable in the acute treatment of migraine.CGRP is a 37 amino acid neuropeptide produced by tissuespecific alternative mRNA splicing of the calcitonin gene (Amara et al., 1982) and is a member of the calcitonin family of peptides, which includes calcitonin, amylin, and adrenomedullin. CGRP activity is mediated by the coexpression of a G-protein-coupled receptor, calcitonin receptor-like receptor, a single transmembrane-spanning protein designated receptor activity-modifying protein (RAMP) 1 (McLatchie et al., 1998), and an intracellular protein, receptor component proArticle, publication date, and citation information can be found at

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Calcitonin gene-related peptide (CGRP) has been implicated in the pathogenesis of migraine. Herein we describe optimization of CGRP receptor antagonists based on an earlier lead structure containing a (3R)-amino-(6S)-phenylcaprolactam core. Replacement of the phenylimidazolinone with an azabenzimidazolone gave stable derivatives with lowered serum shifts. Extensive SAR studies of the C-6 aryl moiety revealed the potency-enhancing effect of the 2,3-difluorophenyl group, and trifluoroethylation of the N-1 amide position resulted in improved oral bioavailabilities, ultimately leading to clinical candidate 38 (MK-0974).

The palladium-catalyzed Suzuki-Miyaura reaction has been utilized as one of the most powerful methods for C-C bond formation. However, Suzuki reactions of electron-deficient 2-heterocyclic boronates generally give low conversions and remain challenging. The successful copper(I) facilitated Suzuki coupling of 2-heterocyclic boronates that is broad in scope is reported. Use of this methodology affords greatly enhanced yields of these notoriously difficult couplings. Furthermore, mechanistic investigations suggest a possible role of copper in the catalytic cycle.

Efficient total syntheses of the C(2)-symmetric (-)-cylindrocyclophanes A and F (1a and 1f) have been achieved. The initial strategy featured the use of a common advanced intermediate to assemble in stepwise fashion the required macrocycle of 1f, exploiting in turn a Myers reductive coupling followed by ring-closing metathesis. In a second-generation strategy, a remarkable cross olefin metathesis dimerization cascade was discovered and exploited to assemble the requisite [7,7]-paracyclophane macrocycles of both 1a and 1f from dienyl monomers. The successful syntheses also featured the effective use of the Danheiser annulation to construct substrates for both the Myers reductive coupling and the metathesis dimerizations strategies. Finally, the Kowalski two-step chain homologation of esters to siloxyalkynes proved superior over the original one-step protocol.

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A fascinating array of architecturally complex natural products arise via dimerization. 1 The vast majority of these structures involve assembly via carbon-heteroatom linkages (e.g., ester, amide, etc.), giving rise to macrocyclic lactones and lactams often possessing C 2 -symmetry. Dimerization via carbon-carbon bond formation, a relatively rare event, not surprisingly furnishes particularly attractive synthetic targets. The cylindrocyclophanes A-F represent such a case. 2 These unique naturally occurring 22-membered carbocyclic [7,7]-paracyclophanes, 3 isolated by Moore and co-workers from Cylindrospermum licheniforme, 2b are postulated to arise biosynthetically via dimerization involving electrophilic aromatic substitution at C(2) of a 5-substituted resorcinol with an olefin appropriately positioned in the side chain. 2c

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