2 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>
Discovery of 8‑Amino-imidazo[1,5‑<i>a</i>]pyrazines as Reversible BTK Inhibitors for the Treatment of Rheumatoid Arthritis
Bruton’s
tyrosine kinase (BTK) is a Tec family kinase with a well-defined role
in the B cell receptor (BCR) pathway. It has become an attractive
kinase target for selective B cell inhibition and for the treatment
of B cell related diseases. We report a series of compounds based
on 8-amino-imidazoÂ[1,5-<i>a</i>]Âpyrazine that are potent
reversible BTK inhibitors with excellent kinase selectivity. Selectivity
is achieved through specific interactions of the ligand with the kinase
hinge and driven by aminopyridine hydrogen bondings with Ser538 and
Asp539, and by hydrophobic interaction of trifluoropyridine in the
back pocket. These interactions are evident in the X-ray crystal structure
of the lead compounds <b>1</b> and <b>3</b> in the complex
with the BTK enzyme. Our lead compounds show desirable PK profiles
and efficacy in the preclinical rat collagen induced arthritis model