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in drug discovery, largely because several thiophene-containing drugs, including tienilic acid and suprofen, have been withdrawn from the market because of toxicities.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. In addition, the glutathione conjugate was detected in bile from a bile duct-cannulated rat study. The structure of the glutathione conjugate was identified by mass spectrometry and (1)H NMR. The glutathione molecule was attached to the thiophene ring, replacing the existing proton. Metabolic phenotyping experiments, using chemical inhibitors or recombinant cytochromes P450 (P450), demonstrated that CYP3A4 was the major P450 enzyme responsible for the metabolic activation, followed by CYP1A2, 2Cs, and 2D6. A novel metabolic activation mechanism is proposed whereby the 2,5-diaminothiophene moiety undergoes oxidation to a 2,5-diimine thiophene reactive intermediate. This mechanism was used to support efforts to eliminate reactive metabolite generation via structural modification of ring substituents using structure-activity relationships. The disruption of formation of the 2,5-diimine reactive intermediate resulted in the elimination of glutathione conjugate formation both in vitro and in vivo and provided a rational approach to mitigating potential safety risks associated with this class of thiophenes in drug research and development.

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.

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.