4 research outputs found
The Discovery of 3‑((4-Chloro-3-methoxyphenyl)amino)-1-((3<i>R</i>,4<i>S</i>)‑4-cyanotetrahydro‑2<i>H</i>‑pyran-3-yl)‑1<i>H</i>‑pyrazole-4-carboxamide, a Highly Ligand Efficient and Efficacious Janus Kinase 1 Selective Inhibitor with Favorable Pharmacokinetic Properties
The
discovery of a potent selective low dose Janus kinase 1 (JAK1)
inhibitor suitable for clinical evaluation is described. As part of
an overall goal to minimize dose, we pursued a medicinal chemistry
strategy focused on optimization of key parameters that influence
dose size, including lowering human Cl<sub>int</sub> and increasing
intrinsic potency, bioavailability, and solubility. To impact these
multiple parameters simultaneously, we used lipophilic ligand efficiency
as a key metric to track changes in the physicochemical properties
of our analogs, which led to improvements in overall compound quality.
In parallel, structural information guided advancements in JAK1 selectivity
by informing on new vector space, which enabled the discovery of a
unique key amino acid difference between JAK1 (Glu966) and JAK2 (Asp939).
This difference was exploited to consistently produce analogs with
the best balance of JAK1 selectivity, efficacy, and projected human
dose, ultimately culminating in the discovery of compound <b>28</b>