title: PF-04859989 as a template for structure-based drug design: identification of new pyrazole series of irreversible KAT II inhibitors with improved lipophilic efficiency.
abstract: 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.
authors: Pfizer Worldwide Research and Development, Neuroscience Medicinal Chemistry, Groton Laboratories, Eastern Point Road, Groton, CT 06340, USA. amy.dounay@coloradocollege.edu
authors: Amy B
authors: AB
authors: Dounay
authors: Marie
authors: M
authors: Anderson
authors: Bruce M
authors: BM
authors: Bechle
authors: Edelweiss
authors: E
authors: Evrard
authors: Xinmin
authors: X
authors: Gan
authors: Ji-Young
authors: JY
authors: Kim
authors: Laura A
authors: LA
authors: McAllister
authors: Jayvardhan
authors: J
authors: Pandit
authors: Suobao
authors: S
authors: Rong
authors: Michelle A
authors: MA
authors: Salafia
authors: Jamison B
authors: JB
authors: Tuttle
authors: Laura E
authors: LE
authors: Zawadzke
authors: Patrick R
authors: PR
authors: Verhoest
mesh_terms: D020134:Catalytic Domain / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions / Q000187:drug effects; D008958:Models, Molecular; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D000637:Transaminases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; C583657:PF-04859989; D011720:Pyrazoles; C031280:pyrazole; D000637:Transaminases; C021481:kynurenine-oxoglutarate transaminase