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

• Published in: Bioorganic & medicinal chemistry letters Vol. 28; no. 20; pp. 3356 - 3362
• Main Authors: Jiang, Jian-kang, Huang, Xiuli, Shamim, Khalida, Patel, Paresma R., Lee, Arthur, Wang, Amy Q., Nguyen, Kimloan, Tawa, Gregory, Cuny, Gregory D., Yu, Paul B., Zheng, Wei, Xu, Xin, Sanderson, Philip, Huang, Wenwei
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.11.2018; Elsevier
• Subjects: Activin Receptors, Type I - antagonists & inhibitors; Activin Receptors, Type I - chemistry; ALK2; Animals; Binding Sites; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Drug Discovery; FOP; Humans; LDN-193189; Life Sciences & Biomedicine; Mice, Inbred C57BL; Molecular Structure; Pharmacology & Pharmacy; Physical Sciences; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - pharmacology; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacokinetics; Pyrazoles - pharmacology; Pyrazolo[1,5-a]pyrimidine; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacokinetics; Pyrimidines - pharmacology; Science & Technology; Structure-Activity Relationship; Sulfamoylnaphthyl; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - pharmacokinetics; Sulfonamides - pharmacology; RLM; SAR; ADME; FOP; Boc; Pyrazolo[1,5-a]pyrimidine; LDN-193189; PAMPA; ALK2; Sulfamoylnaphthyl; Pyrazolo[1,5-alpha]pyrimidine; DORSOMORPHIN; MUTATION; MECHANISMS; BINDING; FIBRODYSPLASIA OSSIFICANS PROGRESSIVA
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2018.09.006

[Display omitted] •Identification of a novel class of 4-sulfamoylnaphthyl series ALK2 inhibitor.•Excellent selectivity for ALK2 over ALK3 with additional overall kinome selectivity.•Key distinctive features identified in the ALK3 homology model to explain ALK2 vs ALK3 selectivity. 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.