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 MK-8318, a Potent and Selective CRTh2 Receptor Antagonist for the Treatment of Asthma
A novel series of
tricyclic tetrahydroquinolines were identified
as potent and selective CRTh2 receptor antagonists. The agonism and
antagonism switch was achieved through structure-based drug design
(SBDD) using a CRTh2 receptor homologue model. The challenge of very
low exposures in pharmacokinetic studies was overcome by exhaustive
medicinal chemistry lead optimization through focused SAR studies
on the tricyclic core. Further optimization resulted in the identification
of the preclinical candidate 4-(cyclopropylÂ((3<i>aS</i>,9<i>R</i>,9<i>aR</i>)-7-fluoro-4-(4-(trifluoromethoxy)Âbenzoyl)-2,3,3<i>a</i>,4,9,9<i>a</i>-hexahydro-1<i>H</i>-cyclopentaÂ[<i>b</i>]Âquinolin-9-yl)Âamino)-4-oxobutanoic acid (<b>15c</b>, <b>MK-8318</b>) with potent and selective CRTh2 antagonist
activity and a favorable PK profile suitable for once daily oral dosing
for potential treatment of asthma