Novel pyrrole carboxamide inhibitors of JAK2 as potential treatment of myeloproliferative disorders. Issue 10 (15th May 2015)

• Record Type: Journal Article
• Authors: Brasca, Maria Gabriella; Gnocchi, Paola; Nesi, Marcella; Amboldi, Nadia; Avanzi, Nilla; Bertrand, Jay; Bindi, Simona; Canevari, Giulia; Casero, Daniele; Ciomei, Marina; Colombo, Nicoletta; Cribioli, Sabrina; Fachin, Gabriele; Felder, Eduard R.; Galvani, Arturo; Isacchi, Antonella; Motto, Ilaria; Panzeri, Achille; Donati, Daniele
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 10(2015)
• Page Start: 2387
• Page End: 2407
• Publication Date: 2015-05-15
• Subjects: JAK2 -- Myeloproliferative disorders -- Protein kinase inhibitor -- Tumour cell proliferation inhibition -- Anti-cancer agents; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2015.03.059
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Deconstruction of compound1 led to the identification of the potent and orally bioavailable JAK2 inhibitor16 (NMS-P830). Abstract: Compound1, a hit from the screening of our chemical collection displaying activity against JAK2, was deconstructed for SAR analysis into three regions, which were explored. A series of compounds was synthesized leading to the identification of the potent and orally bioavailable JAK2 inhibitor16 (NMS-P830), which showed an encouraging tumour growth inhibition in SET-2 xenograft tumour model, with evidence for JAK2 pathway suppression demonstrated by in vivo pharmacodynamic effects.