2 research outputs found
Discovery of a Parenteral Small Molecule Coagulation Factor XIa Inhibitor Clinical Candidate (BMS-962212)
Factor XIa (FXIa)
is a blood coagulation enzyme that is involved
in the amplification of thrombin generation. Mounting evidence suggests
that direct inhibition of FXIa can block pathologic thrombus formation
while preserving normal hemostasis. Preclinical studies using a variety
of approaches to reduce FXIa activity, including direct inhibitors
of FXIa, have demonstrated good antithrombotic efficacy without increasing
bleeding. On the basis of this potential, we targeted our efforts
at identifying potent inhibitors of FXIa with a focus on discovering
an acute antithrombotic agent for use in a hospital setting. Herein
we describe the discovery of a potent FXIa clinical candidate, <b>55</b> (FXIa <i>K</i><sub>i</sub> = 0.7 nM), with excellent
preclinical efficacy in thrombosis models and aqueous solubility suitable
for intravenous administration. BMS-962212 is a reversible, direct,
and highly selective small molecule inhibitor of FXIa
Discovery of Clinical Candidate 2‑((2<i>S</i>,6<i>S</i>)‑2-Phenyl-6-hydroxyadamantan-2-yl)-1-(3′-hydroxyazetidin-1-yl)ethanone [BMS-816336], an Orally Active Novel Selective 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor
BMS-816336
(<b>6n-2</b>), a hydroxy-substituted adamantyl
acetamide, has been identified as a novel, potent inhibitor against
human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1)
enzyme (IC<sub>50</sub> 3.0 nM) with >10000-fold selectivity over
human 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). <b>6n-2</b> exhibits a robust acute pharmacodynamic effect in cynomolgus
monkeys (ED<sub>50</sub> 0.12 mg/kg) and in DIO mice. It is orally
bioavailable (%<i>F</i> ranges from 20 to 72% in preclinical
species) and has a predicted pharmacokinetic profile of a high peak
to trough ratio and short half-life in humans. This ADME profile met
our selection criteria for once daily administration, targeting robust
inhibition of 11β-HSD1 enzyme for the first 12 h period after
dosing followed by an “inhibition holiday” so that the
potential for hypothalamic–pituitary–adrenal (HPA) axis
activation might be mitigated. <b>6n-2</b> was found to be well-tolerated
in phase 1 clinical studies and represents a potential new treatment
for type 2 diabetes, metabolic syndrome, and other human diseases
modulated by glucocorticoid control