Arlene Dietrich

Preparation of L-(Phosphonodifluoromethyl)phenylalanine derivatives as non-hydrolyzable mimetics of O-phosphotyrosine

Abstract N-t-BOC-L-(Phosphonodifluoromethyl)phenylalanine benzyl ester ( 1 ) was prepared in 5 steps from N-t-BOC-L-tyrosine benzyl eser O-triflate ( 4 ). Compound 1 was further converted to derivatives 2 and 3 which are potentially suitable for peptide synthesis. Analogs 1 - 3 are non-hydrolyzable mimetics of O-phosphotyrosine.

Identification of pyridazino[4,5-b]indolizines as selective PDE4B inhibitors.

Substituted pyridazino[4,5-b]indolizines were identified as potent and selective PDE4B inhibitors. We describe the structure-activity relationships generated around an HTS hit that led to a series of compounds with low nanomolar affinity for PDE4B and high selectivity over the PDE4D subtype.

3,4-Dihydropyrimido(1,2-a)indol-10(2H)-ones as potent non-peptidic inhibitors of caspase-3

Cysteine-dependant aspartyl protease (caspase) activation has been implicated as a part of the signal transduction pathway leading to apoptosis. It has been postulated that caspase-3 inhibition could attenuate cell damage after an ischemic event and thereby providing for a novel neuroprotective treatment for stroke. As part of a program to develop a small molecule inhibitor of caspase-3, a novel series of 3,4-dihydropyrimido(1,2-a)indol-10(2H)-ones (pyrimidoindolones) was identified. The synthesis, biological evaluation and structure-activity relationships of the pyrimidoindolones are described.