Journal of Medicinal Chemistry p. 3532 - 3548 (2016)
Update date:2022-09-26
Topics:
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
Villase?or, Armando G.
Yeung, Arthur
Phillips, Gary
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.
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