pf-04859989 and pyrazole

The structure-based design, synthesis, and biological evaluation of a new pyrazole series of irreversible KAT II inhibitors are described herein. The modification of the inhibitor scaffold of 1 and 2 from a dihydroquinolinone core to a tetrahydropyrazolopyridinone core led to discovery of a new series of potent KAT II inhibitors with excellent physicochemical properties. Compound 20 is the most potent and lipophilically efficient of these new pyrazole analogs, with a k(inact)/K(i) value of 112,000 M(-1)s(-1) and lipophilic efficiency (LipE) of 8.53. The X-ray crystal structure of 20 with KAT II demonstrates key features that contribute to this remarkable potency and binding efficiency.

Topics: Catalytic Domain; Crystallography, X-Ray; Dose-Response Relationship, Drug; Drug Design; Enzyme Inhibitors; Humans; Hydrophobic and Hydrophilic Interactions; Models, Molecular; Molecular Structure; Pyrazoles; Structure-Activity Relationship; Transaminases