Discovery of potent, cyclic calcitonin gene-related peptide receptor antagonists.

Calcitonin gene-related peptide (CGRP), a potent dilator of cerebral and dural vasculature, is known to be elevated in plasma and cerebral spinal fluid during migraine attacks. Selective blockade of the CGRP receptor offers the promise of controlling migraine headache more effectively and without the side-effects associated with the use of triptans. Our efforts to develop a novel, peptide-based CGRP antagonist focused on the C-terminal portion of the peptide which is known to bind the receptor but lack agonist properties. Extensive SAR studies of the C-terminal CGRP (27-37) region identified a novel cyclic structure: Bz-Val-Tyr-cyclo[Cys-Thr-Asp-Val-Gly-Pro-Phe-Cys]-Phe-NH(2) (23) with a kb value of 0.126 nM against the cloned human CGRP receptor. Additional SAR studies directed at enhancement of potency and improvement of physicochemical properties yielded a series of analogs with kb values in the 0.05-0.10 nM range.

Irreversible ototoxicity associated with difluoromethylornithine.

Difluoromethylornithine (DFMO) is a potent, irreversible inhibitor of ornithine decarboxylase, the rate-limiting enzyme in the synthesis of polyamines that promote cellular proliferation. DFMO has been tested as a potential cancer therapeutic and chemopreventive agent in clinical trials. Reversible hearing loss is a recognized toxicity of DFMO that usually occurs at doses above 2 g/m(2)/d, and generally when the cumulative dose exceeds 250 g/m(2). In a recently completed Barrett's esophagus chemoprevention trial, a participant developed a 15-dB decrease in hearing at frequencies of 250, 2,000, and 3,000 Hz in the right ear and a > or =20-dB decrease in hearing at 4,000 to 6,000 Hz in the left ear after taking 0.5 g/m(2)/d DFMO for approximately 13 weeks (cumulative dose of 45 g/m(2)). The threshold shifts persisted 7 months after DFMO was discontinued. There was no obvious impact on the participant's clinical hearing, but these findings were consistent with irreversible hearing loss. This is the first case reported of irreversible ototoxicity in a clinical trial participant receiving DFMO and, thus, trial participants should be made aware of this small but important risk.