Design and Synthesis of Pyrazole-Based Macrocyclic Kinase Inhibitors Targeting BMPR2

ACS Medicinal Chemistry Letters
2023.0

Abstract

Bone morphogenetic protein (BMP) signaling is mediated by transmembrane protein kinases that form heterotetramers consisting of type-I and type-II receptors. Upon BMP binding, the constitutively active type-II receptors activate specific type-I receptors by transphosphorylation, resulting in the phosphorylation of SMAD effector proteins. Drug discovery in the receptor tyrosine kinase-like (TKL) family has largely focused on type-I receptors, with few inhibitors that have been published targeting type-II receptors. BMPR2 is involved in several diseases, most notably pulmonary arterial hypertension, but also contributes to Alzheimer's disease and cancer. Here, we report that macrocyclization of the promiscuous inhibitor <b>1</b>, based on a 3-amino-1<i>H</i>-pyrazole hinge binding moiety, led to a selective and potent BMPR2 inhibitor <b>8a</b>.

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