Douglas M. Kalvin

Potent and orally bioavailable noncysteine-containing inhibitors of protein farnesyltransferase.

Potent and orally bioavailable nonthiol-containing inhibitors of protein farnesyltransferase are described. Oral bioavailability was achieved by replacement of the pyridyl ether moiety of 1 with a 2-substituted furan ether to give 4. Potency was regained with 2,5-disubstituted furan ethers while maintaining the bioavailability inherent in 4. p-Chlorophenylfuran ether 24 is 0.7 nM in vitro (FTase) and is 32% bioavailable in the mouse, 30% bioavailable in rats, and 21% bioavailable in dogs.

Scaffold oriented synthesis. Part 4: Design, synthesis and biological evaluation of novel 5-substituted indazoles as potent and selective kinase inhibitors employing heterocycle forming and multicomponent reactions

We report the synthesis and biological evaluation of 5-substituted indazoles as kinase inhibitors. The compounds were synthesized in a parallel synthesis fashion from readily available starting materials employing heterocycle forming and multicomponent reactions and were evaluated against a panel of kinase assays. Potent inhibitors were identified for Gsk3β, Rock2, and Egfr.

Scaffold oriented synthesis. Part 3: Design, synthesis and biological evaluation of novel 5-substituted indazoles as potent and selective kinase inhibitors employing [2+3] cycloadditions

We report the synthesis and biological evaluation of 5-substituted indazoles and amino indazoles as kinase inhibitors. The compounds were synthesized in a parallel synthesis fashion from readily available starting materials employing [2+3] cycloaddition reactions and were evaluated against a panel of kinase assays. Potent inhibitors were identified for numerous kinases such as Rock2, Gsk3β, Aurora2 and Jak2.