SAR and in vivo evaluation of 4-aryl-2-aminoalkylpyrimidines as potent and selective Janus kinase 2 (JAK2) inhibitors.

We report the discovery of a series of 4-aryl-2-aminoalkylpyrimidine derivatives as potent and selective JAK2 inhibitors. High throughput screening of our in-house compound library led to the identification of hit 1, from which optimization resulted in the discovery of highly potent and selective JAK2 inhibitors. Advanced lead 10d demonstrated a significant dose-dependent pharmacodynamic and antitumor effect in a mouse xenograft model.

Discovery of a novel series of potent and orally bioavailable phosphoinositide 3-kinase γ inhibitors.

The phosphoinositide 3-kinases (PI3Ks) have been linked to an extraordinarily diversified group of cellular functions making these enzymes compelling targets for the treatment of disease. A large body of evidence has linked PI3Kγ to the modulation of autoimmune and inflammatory processes making it an intriguing target for drug discovery. Our high-throughput screening (HTS) campaign revealed two hits that were nominated for further optimization studies.

Synthesis and Electrochemical Studies of a Series of Fluorinated Dodecaphenylporphyrins.

Dodecaphenylporphyrins with varying degrees of fluorination of the peripheral phenyl rings (F(x)()DPPs) were synthesized as model compounds for studying electronic effects in nonplanar porphyrins, and detailed electrochemical studies of the chloroiron(III) complexes of these compounds were undertaken. The series of porphyrins, represented as FeDPPCl and as FeF(x)()DPPCl where x = 4, 8 (two isomers), 12, 20, 28, or 36, could be reversibly oxidized by two successive one-electron transfer steps in dichloromethane to give pi-cation radicals and pi-dications, respectively. All of the compounds investigated could also be reduced by three electrons in benzonitrile or pyridine.

Comparative Analysis of the Conformations of Symmetrically and Asymmetrically Deca- and Undecasubstituted Porphyrins Bearing Meso-Alkyl or -Aryl Groups.

Conformational analysis of highly substituted porphyrins has potential implications for modeling the behavior of macrocycles in tetrapyrrole-containing protein complexes and during catalytic reactions. In order to study the influence of different substituent patterns on the conformation of the porphyrin macrocycle, a series of metal free and nickel(II) decasubstituted porphyrins bearing aryl or ethyl groups at opposite meso positions and alkyl groups at the pyrrole positions have been synthesized and characterized by X-ray crystallography. Crystal structures of the free-base porphyrins with 5,15-diaryl substituents showed negligible out-of-plane distortion but a large amount of in-plane distortion along the 5,15-axis accompanied by large bond angle changes similar to those previously seen for related porphyrins with 5,15-dialkyl substituents.