On-resin N-methylation of cyclic peptides for discovery of orally bioavailable scaffolds.

Backbone N-methylation is common among peptide natural products and has a substantial impact on both the physical properties and the conformational states of cyclic peptides. However, the specific impact of N-methylation on passive membrane diffusion in cyclic peptides has not been investigated systematically. Here we report a method for the selective, on-resin N-methylation of cyclic peptides to generate compounds with drug-like membrane permeability and oral bioavailability. The selectivity and degree of N-methylation of the cyclic peptide was dependent on backbone stereochemistry, suggesting that conformation dictates the regiochemistry of the N-methylation reaction. The permeabilities of the N-methyl variants were corroborated by computational studies on a 1,024-member virtual library of N-methyl cyclic peptides. One of the most permeable compounds, a cyclic hexapeptide (molecular mass = 755 Da) with three N-methyl groups, showed an oral bioavailability of 28% in rat

On-resin N-methylation of cyclic peptides for discovery of orally bioavailable scaffolds

Backbone N-methylation is common among peptide natural products and has a significant impact on both the physical properties and the conformational states of cyclic peptides. However, the specific impact of N-methylation on passive membrane diffusion in cyclic peptides has not been investigated systematically. Here we report a method for the selective, on-resin N-methylation of cyclic peptides to generate compounds with drug-like membrane permeability and oral bioavailability. The selectivity and degree of N-methylation of the cyclic peptide was determined by backbone stereochemistry, suggesting that conformation dictates the regiochemistry of the N-methylation reaction. The permeabilities of the N-methyl variants were corroborated by computational studies on a 1024-member virtual library of N-methyl cyclic peptides. One of the most permeable compounds, a cyclic hexapeptide (MW = 755) with three N-methyl groups, showed an oral bioavailability of 28% in rat

Deep brain stimulation: indications and evidence.

Deep brain stimulation is a minimally invasive targeted neurosurgical intervention that enables structures deep in the brain to be stimulated electrically by an implanted pacemaker. It has become the treatment of choice for Parkinson's disease, refractory to, or complicated by, drug therapy. Its efficacy has been demonstrated robustly by randomized, controlled clinical trials, with multiple novel brain targets having been discovered in the last 20 years. Multifarious clinical indications for deep brain stimulation now exist, including dystonia and tremor in movement disorders; depression, obsessive-compulsive disorder and Tourette's syndrome in psychiatry; epilepsy, cluster headache and chronic pain, including pain from stroke, amputation, trigeminal neuralgia and multiple sclerosis. Current research argues for novel indications, including hypertension and orthostatic hypotension. The development, principles, indications and effectiveness of the technique are reviewed here. While deep brain stimulation is a standard and widely accepted treatment for Parkinson's disease after 20 years of experience, in chronic pain it remains restricted to a handful of experienced, specialist centers willing to publish outcomes despite its use for over 50 years. Reasons are reviewed and novel approaches to appraising clinical evidence in functional neurosurgery are suggested