Discovery of Potent and Selective Pyrazolopyrimidine Janus Kinase 2 Inhibitors

Abstract

The discovery of somatic Jak2 mutations in patients with chronic myeloproliferative neoplasms has led to significant interest in discovering selective Jak2 inhibitors for use in treating these disorders. A high-throughput screening effort identified the pyrazolo[1,5-a]pyrimidine scaffold as a potent inhibitor of Jak2. Optimization of lead compounds 7a-b and 8 in this chemical series for activity against Jak2, selectivity against other Jak family kinases, and good in vivo pharmacokinetic properties led to the discovery of 7j. In a SET2 xenograft model that is dependent on Jak2 for growth, 7j demonstrated a time-dependent knock-down of pSTAT5, a downstream target of Jak2.

4‐Arylation of N‐Acylamino‐ and Aminopyrazoles by the Suzuki–Miyaura Cross‐Coupling Reaction

“…Furthermore, no systematic study including reaction optimization and exploration of the substrate scope has been disclosed. [34] Poorly explored cross-coupling methodologies in this field and the potential bioactivity of the target arylated aminopyrazoles encouraged us to further explore the arylation of aminopyrazole derivatives at the 4-position. Herein, we present our results of the Pd-catalyzed C-C cross-coupling reactions of pyrazoles with a range of aryl-, heteroaryl-, and styrylboronic acids or esters.…”

Characterization of the aminopyridine derivative KRC-180 as a JAK2 inhibitor

“…The high resolution (2.30 Å) crystal structure of human JAK2 in complex with an inhibitor, N-[1-(3-chlorophenyl)-3-methyl-1H-pyrazol-5-yl] pyrazolo [1,5-a] pyrimidine-3-carboxamide, was downloaded from the RCSB Protein Data Bank (PDB code: 4HGE) (17). For protein preparation, the active site for docking was identified from the binding site of the inhibitor in the co-crystal structure.…”

Selective JAK Inhibitors

“…A series of pyrazolopyrimidine compounds was reported by Genetech as being potent JAK2 inhibitors with moderate to good selectivity [39]. The X-ray structure of an earlier lead compound, 27, bound to JAK2 showed several key interactions that led to more potent compounds.…”

“…S*BIO (Singapore) described a series of macrocyclic aminopyrimidines as being selective JAK2/TYK2/FLT3 inhibitors [49][50][51][52]. Through extensive modeling studies, pacritinib (SB1518, 38) and SB1578 (39) were shown to bind to the hinge of the kinase via their aminopyrimidine moieties [53]. They both make a further hydrogen bond to the kinase from their benzylic oxygens to Ser-936.…”