2. Academic Validation
  3. Discovery of 3-(4-sulfamoylnaphthyl)pyrazolo[1,5-a]pyrimidines as potent and selective ALK2 inhibitors

Discovery of 3-(4-sulfamoylnaphthyl)pyrazolo[1,5-a]pyrimidines as potent and selective ALK2 inhibitors

  • Bioorg Med Chem Lett. 2018 Nov 1;28(20):3356-3362. doi: 10.1016/j.bmcl.2018.09.006.
Jian-Kang Jiang 1,  Xiuli Huang 2,  Khalida Shamim 2,  Paresma R Patel 2,  Arthur Lee 2,  Amy Q Wang 2,  Kimloan Nguyen 2,  Gregory Tawa 2,  Gregory D Cuny 3,  Paul B Yu 4,  Wei Zheng 2,  Xin Xu 2,  Philip Sanderson 2,  Wenwei Huang 5
Affiliations

Affiliations

  • 1 National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Bethesda, MD 20892-3370, USA. Electronic address: [email protected].
  • 2 National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Bethesda, MD 20892-3370, USA.
  • 3 Department of Pharmacological and Pharmaceutical Sciences, University of Houston, 4849 Calhoun Road, Health Building 2, Room, 7036, Houston, TX 77204, USA.
  • 4 Brigham and Women's Hospital and Harvard Medical School, Division of Cardiovascular Medicine, 20 Shattuck Street, Thorn Biosciences 1219, Boston, MA 02115, USA.
  • 5 National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Bethesda, MD 20892-3370, USA. Electronic address: [email protected].
PMID: 30227946 DOI: 10.1016/j.bmcl.2018.09.006
Abstract

The pyrazolo[1,5-a]pyrimidine LDN-193189 is a potent inhibitor of activin receptor-like kinase 2 (ALK2) but is nonselective for highly homologous ALK3 and shows only modest kinome selectivity. Herein, we describe the discovery of a novel series of potent and selective ALK2 inhibitors by replacing the quinolinyl with a 4-(sulfamoyl)naphthyl, yielding ALK2 inhibitors that exhibit not only excellent discrimination versus ALK3 but also high kinome selectivity. In addition, the optimized compound 23 demonstrates good ADME and in vivo pharmacokinetic properties.

Keywords

ALK2; FOP; LDN-193189; Pyrazolo[1,5-a]pyrimidine; Sulfamoylnaphthyl.

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