2,4-Diamino-8-quinazoline carboxamides as novel, potent inhibitors of the NAD hydrolyzing enzyme CD38: Exploration of the 2-position structure-activity relationships

• Published in: Bioorganic & medicinal chemistry Vol. 26; no. 8; pp. 2107 - 2150
• Main Authors: Deaton, David N., Haffner, Curt D., Henke, Brad R., Jeune, Michael R., Shearer, Barry G., Stewart, Eugene L., Stuart, J. Darren, Ulrich, John C.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-05-2018
• Subjects: ADP-ribosyl Cyclase 1 - antagonists & inhibitors; ADP-ribosyl Cyclase 1 - metabolism; Amides - chemistry; Amides - metabolism; Amides - pharmacokinetics; Animals; Binding Sites; CD38; CD38 inhibitor; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacokinetics; Half-Life; Humans; Mice; Molecular Docking Simulation; NAD; NAD - chemistry; NAD - metabolism; NAD glycohydrolase; Nicotinamide adenine dinucleotide; Protein Structure, Tertiary; Quinazolines - chemistry; Structure-Activity Relationship; NAD; CD38 inhibitor; Nicotinamide adenine dinucleotide; CD38; NAD glycohydrolase
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2018.03.021

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Starting from 4-amino-8-quinoline carboxamide lead 1a and scaffold hopping to the chemically more tractable quinazoline, a systematic exploration of the 2-substituents of the quinazoline ring, utilizing structure activity relationships and conformational constraint, resulted in the identification of 39 novel CD38 inhibitors. Eight of these analogs were 10–100-fold more potent human CD38 inhibitors, including the single digit nanomolar inhibitor 1am. Several of these molecules also exhibited improved therapeutic indices relative to hERG activity. A representative analog 1r exhibited suitable pharmacokinetic parameters for in vivo animal studies, including moderate clearance and good oral bioavailability. These inhibitor compounds will aid in the exploration of the enzymatic functions of CD38, as well as furthering the study of the therapeutic implications of NAD enhancement in metabolic disease models.