Aminopyridinecarboxamide-based inhaled IKK-2 inhibitors for asthma and COPD: Structure-activity relationship.

Installation of sites for metabolism in the lead compound PHA-767408 was the key focus of the IKK-2 inhaled program. This paper reports our efforts to identify a novel series of aminopyridinecarboxamide-based IKK-2 inhibitors, which display low nanomolar potency against IKK-2 with long duration of action (DOA), and metabolically labile to phase I and/or phase II metabolizing enzymes with potential capability for multiple routes of clearance. Several compounds have demonstrated their potential usefulness in the treatment of asthma and chronic obstructive pulmonary disease (COPD).

Novel metabolic bioactivation mechanism for a series of anti-inflammatory agents (2,5-diaminothiophene derivatives) mediated by cytochrome p450 enzymes.

The thiophene moiety is considered a structural alert in molecular design in drug discovery, largely because several thiophene-containing drugs, including tienilic acid and suprofen, have been withdrawn from the market because of toxicities. Reactive thiophene intermediates, activated via sulfur oxidation or ring epoxidation, are possible culprits for these adverse side effects. In this work, the metabolic activation of an anti-inflammatory agent, 1-(3-carbamoyl-5-(2,3,5-trichlorobenzamido)thiophen-2-yl)urea), containing a 2,5-diaminothiophene structure, was studied in liver microsomes in the presence of glutathione or N-acetylcysteine as trapping agents.

Inhibitors of HCV NS5B polymerase. Part 2: Evaluation of the northern region of (2Z)-2-benzoylamino-3-(4-phenoxy-phenyl)-acrylic acid.

A novel series of non-nucleoside HCV NS5B polymerase inhibitors was prepared from a (2Z)-2-benzoylamino-3-(4-phenoxy-phenyl)-acrylic acid template. Solution and solid phase analog synthesis focused on the northern region of the template combined with structure based design led to the discovery of several potent and orally bioavailable lead compounds.

Short Enantioselective Total Syntheses of the Piperidine Alkaloids (S)-Coniine and (2R,6R)-trans-Solenopsin A via Catalytic Asymmetric Imine Hydrosilylation.

The enantioselective syntheses of (S)-coniine and (2R,6R)-trans-solenopsin A are reported. The key step in both syntheses is the catalytic asymmetric hydrosilylation of a cyclic imine.