PF-04859989 as a template for structure-based drug design: identification of new pyrazole series of irreversible KAT II inhibitors with improved lipophilic efficiency.
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.
T1 T2 T3 T4 T5 T6 T7 T8 T9 T10
CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL GENE-Y GENE-Y GENE-Y GENE-Y
dihydroquinolinone tetrahydropyrazolopyridinone pyrazole pyrazole PF-04859989 pyrazole KAT II KAT II KAT II KAT II