John Michael Morin

γ-Lactam analogues of the penems

Abstract Racemic γ-lactam analogues of the penems have been prepared and tested for biological activity. The 7-acylamino derivatives exhibited low levels of antibiotic activity.

Ion channel screening.

Ion channels are attractive targets for drug discovery with recent estimates indicating that voltage and ligand-gated channels account for the third and fourth largest gene families represented in company portfolios after the G protein coupled and nuclear hormone receptor families. A historical limitation on ion channel targeted drug discovery in the form of the extremely low throughput nature of the gold standard assay for assessing functional activity, patch clamp electrophysiology in mammalian cells, has been overcome by the implementation of multi-well plate format cell-based screening strategies for ion channels. These have taken advantage of various approaches to monitor ion flux or membrane potential using radioactive, non-radioactive, spectroscopic and fluorescence measurements and have significantly impacted both high-throughput screening and lead optimization efforts. In addition, major advances have been made in the development of automated electrophysiological platforms to increase capacity for cell-based screening using formats aimed at recapitulating the gold standard assay. This review addresses the options available for cell-based screening of ion channels with examples of their utility and presents case studies on the successful implementation of high-throughput screening campaigns for a ligand-gated ion channel using a fluorescent calcium indicator, and a voltage-gated ion channel using a fluorescent membrane potential sensitive dye.

Fused bicyclic Gly-Asp β-turn mimics with potent affinity for GPIIb-IIIa. Exploration of the arginine isostere

6-[4-Amidinobenzoyl]amino]-tetralone-2-acetic acid is a potent antagonist of GPIIb-IIIa. Substitution in the meta position of the benzamidine, or replacement with a heteroaryl amidine was tolerated in this series. Use of an acyl-linked 4-alkyl piperidine as an arginine isostere also provided active compounds. Compounds from this series provided substantial systemic exposure in the rat following oral administration.

Rearrangement of exomethylenecephams to homocephams

Exomethylenecephans rearrange by reaction with diazo compounds in the presence of cupric sulfate to generaye the homocepham ring-system

An Improved Process for the Preparation of Oxazolino-azetidinones and 1-Oxadethiacephams from Exomethylenecepham Sulfoxides

Abstract Oxazolino-azetidinones and 1-oxadethiacephams have been prepared in one and two steps, respectively, from exomethylene-cepham sulfoxides.