PF-04859989 as a template for structure-based drug design: Identification of new pyrazole series of irreversible KAT II inhibitors with improved lipophilic efficiency

• Published in: Bioorganic & medicinal chemistry letters Vol. 23; no. 7; pp. 1961 - 1966
• Main Authors: Dounay, Amy B., Anderson, Marie, Bechle, Bruce M., Evrard, Edelweiss, Gan, Xinmin, Kim, Ji-Young, McAllister, Laura A., Pandit, Jayvardhan, Rong, SuoBao, Salafia, Michelle A., Tuttle, Jamison B., Zawadzke, Laura E., Verhoest, Patrick R.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.04.2013; Elsevier
• Subjects: Catalytic Domain - drug effects; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Crystallography, X-Ray; Dose-Response Relationship, Drug; Drug Design; drugs; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Hydrophobic and Hydrophilic Interactions - drug effects; Irreversible inhibitor; Kynurenic acid; Kynurenine aminotransferase; Kynurenine pathway; Life Sciences & Biomedicine; Lipophilic efficiency; Mechanism-based inactivator; Models, Molecular; Molecular Structure; Pharmacology & Pharmacy; Physical Sciences; physicochemical properties; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; Schizophrenia; Science & Technology; Structure-Activity Relationship; Transaminases - antagonists & inhibitors; Transaminases - metabolism; X-ray diffraction; Irreversible inhibitor; Lipophilic efficiency; Kynurenine aminotransferase; Mechanism-based inactivator; Schizophrenia; Kynurenic acid; Kynurenine pathway; ACID; CRYSTAL-STRUCTURE; CEREBROSPINAL-FLUID; DISCOVERY; REDUCTION; ELEVATED LEVELS; KYNURENINE AMINOTRANSFERASE-II
• ISSN: 0960-894X; 1464-3405; 1464-3405
• DOI: 10.1016/j.bmcl.2013.02.039

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 kinact/Ki value of 112,000M−1s−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.