13 research outputs found
Identification of Imidazo-Pyrrolopyridines as Novel and Potent JAK1 Inhibitors
A therapeutic rationale is proposed for the treatment
of inflammatory diseases, such as rheumatoid arthritis (RA), by specific
targeting of the JAK1 pathway. Examination of the preferred binding
conformation of clinically effective, pan-JAK inhibitor <b>1</b> led to identification of a novel, tricyclic hinge binding scaffold <b>3</b>. Exploration of SAR through a series of cycloamino and cycloalkylamino
analogues demonstrated this template to be highly tolerant of substitution,
with a predisposition to moderate selectivity for the JAK1 isoform
over JAK2. This study culminated in the identification of subnanomolar
JAK1 inhibitors such as <b>22</b> and <b>49</b>, having
excellent cell potency, good rat pharmacokinetic characteristics,
and excellent kinase selectivity. Determination of the binding modes
of the series in JAK1 and JAK2 by X-ray crystallography supported
the design of analogues to enhance affinity and selectivity
Discovery of Potent and Selective Pyrazolopyrimidine Janus Kinase 2 Inhibitors
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 pyrazoloÂ[1,5-<i>a</i>]Âpyrimidine
scaffold as a potent inhibitor of Jak2. Optimization of lead compounds <b>7a</b>–<b>b</b> and <b>8</b> 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 <b>7j</b>. In a SET2 xenograft model that is dependent on
Jak2 for growth, <b>7j</b> demonstrated a time-dependent knock-down
of pSTAT5, a downstream target of Jak2