3 research outputs found
Structure-Based Design of Macrocyclic Factor XIa Inhibitors: Discovery of the Macrocyclic Amide Linker
A novel series of macrocyclic FXIa
inhibitors was designed based
on our lead acyclic phenyl imidazole chemotype. Our initial macrocycles,
which were double-digit nanomolar FXIa inhibitors, were further optimized
with assistance from utilization of structure-based drug design and
ligand bound X-ray crystal structures. This effort resulted in the
discovery of a macrocyclic amide linker which was found to form a
key hydrogen bond with the carbonyl of Leu41 in the FXIa active site,
resulting in potent FXIa inhibitors. The macrocyclic FXIa series,
exemplified by compound <b>16</b>, had a FXIa <i>K</i><sub>i</sub> = 0.16 nM with potent anticoagulant activity in an in
vitro clotting assay (aPTT EC<sub>1.5x</sub> = 0.27 ÎĽM) and
excellent selectivity against the relevant blood coagulation enzymes
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