Discovery of heterocyclic ureas as a new class of raf kinase inhibitors: identification of a second generation lead by a combinatorial chemistry approach.

Heterocyclic ureas, such as N-3-thienyl N'-aryl ureas, have been identified as novel inhibitors of raf kinase, a key mediator in the ras signal transduction pathway. Structure-activity relationships were established, and the potency of the screening hit was improved 10-fold to IC(50)=1.7 microM. A combinatorial synthesis approach enabled the identification of a breakthrough lead (IC(50)=0.54 microM) for a second generation series of heterocyclic urea raf kinase inhibitors.

Discovery of a new class of p38 kinase inhibitors.

The MAP kinase p38 has been implicated in cytokine signaling, and its inhibitors are potentially useful for the treatment of arthritis and osteoporosis. Novel small-molecule inhibitors of p38 kinase were derived from a combinatorial chemistry effort and exhibit activity in the nanomolar range. Very steep structure-activity relationships are observed within this class.

1-Phenyl-5-pyrazolyl ureas: potent and selective p38 kinase inhibitors.

Inhibitors of the MAP kinase p38 are potentially useful for the treatment of arthritis and osteoporosis. Several 2,3-dichlorophenyl ureas were identified as small-molecule inhibitors of p38 by a combinatorial chemistry effort. Optimization for cellular potency led to the discovery of a new class of potent and selective p38 kinase inhibitors, exemplified by the 1-phenyl-5-pyrazolyl urea 7 (IC50 = 13 nM).

Vicinal tetrahydrofuranyl substitution of alkyl chains. Tetra-, penta-, and hexafunctionalized arrays.

The tetrakis (tetrahydrofuranyl) dialdehydes 14 and 19 are accessible by oxidative cleavage of extensively substituted cyclohexenes, which have in turn been assembled in a stereocontrolled manner. Reaction of 14 with an excess of the Normant reagent followed by ring closure resulted in conversion to the hexafunctionalized polyether 15. Allylindation of the same dialdehyde gave rise to lactol 16, a reactivity pattern that was essentially duplicated when 19 was treated with the Normant reagent. Attempts to add allylmagnesium bromide to 19 resulted in operation of a Tishchenko reaction with formation of lactone 23. By means of X-ray diffraction analysis, it was possible to ascertain the conformation adopted by 20 and 23 in the solid state. In addition, 15 was shown to populate a conformation in which the oxygen are very predominantly in gauche arrangements, this structural preorganization taking place in the absence of any metal ions.