Herein we report investigations into the p38alpha MAP kinase activity of trisubstituted imidazoles that led to the identification of compounds possessing highly potent in vivo activity. The SAR of a novel series of imidazopyridines is demonstrated as well, resulting in compounds possessing cellular potency and enhanced in vivo activity in the rat collagen-induced arthritis model of chronic inflammation.

Three novel, optically active, 6-substituted 2-(aminomethyl)chromans were synthesized from readily available chroman 2-carboxylic acid precursors. These chroman-containing primary amines are useful building blocks for the synthesis of chroman-derived pharmaceutical agents. (C) 2004 Elsevier Ltd. All rights reserved.

A general and practical synthetic method was developed for indoline-5-sulfonic acids hearing a thiazole heterocycle attached to the nitrogen atom. Two select sulfonic acids were further converted to their corresponding sulfonyl chlorides, key intermediates to the indoline-5-sulfonamide pharmacophore.

Inhibitors of the MAP kinase p38 are potentially useful for the treatment for osteoporosis, arthritis, and other inflammatory diseases. A series of thienyl, furyl, and pyrrolyl ureas has been identified as potent p38 inhibitors, displaying in vitro activity in the nanomolar range.

Potential protease inhibitors are formed stereoselectively by a reaction sequence that begins with the conversion of N-protected alpha-amino aldehydes with the homoenolate reagent 1. The lactones 2 thus formed may be coupled with alpha-amino acid amides by a new variation of the Weinreb method in which dialkylaluminum amides are used as ring-opening agents. In this way for diastereomers of the compounds 3 belonging to the PSI-Phe[CHOHCH progroup are formed. R = CF3CO, Cb = C(C = O)NiPr2, Bn = PhCH2.

Potentielle Proteaseinhibitoren entstehen stereoselektiv am Ende einer Reaktionssequenz, die mit der Umsetzung N‐geschützter α‐Aminoaldehyde mit dem Homoenolat‐Reagens 1 beginnt. Die dabei gebildeten Lactone 2 lassen sich durch eine neue Variante der Weinreb‐Methode, bei der Dialkylaluminiumamide als ringöffnende Reagentien eingesetzt werden, mit α‐Aminosäureamiden kuppeln. So entstehen vier Diastereomere der Verbindungen 3, die zur Ψ‐Phe‐[CHOHCH]Pro‐Gruppe gehören. R  CF3CO, Cb  C(CO)NiPr2, Bn  PhCH2.magnified image

A rapid sensitive method for the quantification of in vitro HIV-protease activity has been developed on the basis of the endoproteolytic conversion of N-Dns-SQNYPIV to N-Dns-SQNY. The use of the N-dansyl group as a fluorescence label was shown to not significantly alter the apparent kinetic parameters for the peptideenzyme interaction. Using fluorescence detection, the dansylated product and unconverted substrate are detected in a single rapid (3 min) isocratic reverse-phase HPLC separation in quantities as low as 0.2 pmol. The method is highly reproducible and suited to a variety of applications including the analysis of large sample numbers and rigorous enzymological studies.