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

Jennifer A Amrhein; Guiqun Wang; Benedict-Tilman Berger; Lena M Berger; Amalia D Kalampaliki; Andreas Krämer; Stefan Knapp; Thomas Hanke

doi:10.1021/acsmedchemlett.3c00127

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

ACS Med Chem Lett. 2023 May 30;14(6):833-840. doi: 10.1021/acsmedchemlett.3c00127. eCollection 2023 Jun 8.

Authors

Jennifer A Amrhein^{1

2}, Guiqun Wang^{1

2

3}, Benedict-Tilman Berger^{1

2}, Lena M Berger^{1

2}, Amalia D Kalampaliki⁴, Andreas Krämer^{1

2

3}, Stefan Knapp^{1

2

3}, Thomas Hanke^{1

2}

Affiliations

¹ Institute for Pharmaceutical Chemistry, Johann Wolfgang Goethe-University, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.
² Structure Genomics Consortium, Buchmann Institute for Molecular Life Sciences, Johann Wolfgang Goethe-University, Max-von-Laue-Str. 15, D-60438 Frankfurt am Main, Germany.
³ German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), DKTK Site Frankfurt-Mainz, 69120 Heidelberg, Germany.
⁴ Department of Pharmacy, Division of Pharmaceutical Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, Zografou, 15771 Athens, Greece.

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 1, based on a 3-amino-1H-pyrazole hinge binding moiety, led to a selective and potent BMPR2 inhibitor 8a.