2,4,6-Triaminopyrimidine as a Novel Hinge Binder in a Series of PI3Kδ Selective Inhibitors

• Published in: Journal of medicinal chemistry Vol. 59; no. 7; pp. 3532 - 3548
• Main Authors: Patel, Leena, Chandrasekhar, Jayaraman, Evarts, Jerry, Haran, Aaron C, Ip, Carmen, Kaplan, Joshua A, Kim, Musong, Koditek, David, Lad, Latesh, Lepist, Eve-Irene, McGrath, Mary E, Novikov, Nikolai, Perreault, Stephane, Puri, Kamal D, Somoza, John R, Steiner, Bart H, Stevens, Kirk L, Therrien, Joseph, Treiberg, Jennifer, Villaseñor, Armando G, Yeung, Arthur, Phillips, Gary
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 14.04.2016; Amer Chemical Soc
• Subjects: Animals; Arthritis, Experimental - chemically induced; Arthritis, Experimental - drug therapy; Arthritis, Experimental - enzymology; B-Lymphocytes - cytology; B-Lymphocytes - drug effects; B-Lymphocytes - enzymology; Cells, Cultured; Chemistry, Medicinal; Class I Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Collagen - toxicity; Crystallography, X-Ray; Disease Models, Animal; Female; Hepatocytes - drug effects; Hepatocytes - enzymology; Humans; Life Sciences & Biomedicine; Microsomes, Liver - drug effects; Microsomes, Liver - enzymology; Models, Molecular; Pharmacology & Pharmacy; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - pharmacology; Pyrimidines - chemistry; Pyrimidines - pharmacokinetics; Pyrimidines - pharmacology; Quinazolinones - chemistry; Quinazolinones - pharmacokinetics; Quinazolinones - pharmacology; Rats; Rats, Inbred Lew; Science & Technology; Tissue Distribution; B-CELLS; PI3K; METABOLISM; IDELALISIB; DELTA; ALDEHYDE OXIDASE; MECHANISMS; ARTHRITIS; PHOSPHOINOSITIDE 3-KINASE; DISCOVERY
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.6b00213

Inhibition of phosphoinositide 3-kinase δ (PI3Kδ) is an appealing target for several hematological malignancies and inflammatory diseases. Herein, we describe the discovery and optimization of a series of propeller shaped PI3Kδ inhibitors comprising a novel triaminopyrimidine hinge binder. Combinations of electronic and structural strategies were employed to mitigate aldehyde oxidase mediated metabolism. This medicinal chemistry effort culminated in the identification of 52, a potent and highly selective inhibitor of PI3Kδ that demonstrates efficacy in a rat model of arthritis.