Arylglycine derivatives as potent transient receptor potential melastatin 8 (TRPM8) antagonists.

A series of arylglycine-based analogs was synthesized and tested for TRPM8 antagonism in a cell-based functional assay. Following structure-activity relationship studies in vitro, a number of compounds were identified as potent TRPM8 antagonists and were subsequently evaluated in an in vivo pharmacodynamic assay of icilin-induced 'wet-dog' shaking in which compound 12 was fully effective. TRPM8 antagonists of the type described here may be useful in treating pain conditions wherein cold hypersensitivity is a dominant feature.

Synthesis and antibacterial activity of C6-carbazate ketolides.

A novel series of ketolides containing heteroaryl groups that are linked to the erythronolide ring via a C6-carbazate functionality has been successfully synthesized. Careful modulation of the heteroaryl groups, the length and degree of saturation of the C6-carbazate linker, and the substituents present on each of the carbazate nitrogens led to compounds with potent activity against key bacterial respiratory pathogens. The best analogs of this series had in vitro and in vivo (sc dosing) profiles that were comparable to telithromycin.

Relay ring-closing metathesis (RRCM): a strategy for directing metal movement throughout olefin metathesis sequences.

The title concept involves the use of structurally modified RCM substrates that contain extender arms, terminating in a remote reactive alkene. Initiation of an RCM sequence at that reactive alkene is followed by rapid intramolecular relay of the metal center to an initially less reactive alkene in the parent substrate. This permits one to control the relative timing (or direction) of a metathesis sequence. For example, one can reverse the inherent tendency of an unsymmetrical alpha,omega-diene substrate to close, say, left-to-right, to that of right-to-left. Four distinct types of application of the RRCM concept are demonstrated. Among other things, they show the preparation of tetrasubstituted electron-deficient alkenes using G1 [(Cy3P)2(Cl2)Ru=CHPh], complementary control of directionality (endedness), auxiliary benefits (enzyme specificity) from the incorporation of additional steric bulk, the activation of otherwise ineffective substrates for RCM closure, the use of unorthodox alkenes as initiation sites for ring closure, and control of product olefin geometry.