7 research outputs found
Optimization of 1,2,4-Triazolopyridines as Inhibitors of Human 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD-1)
Small
alkyl groups and spirocyclic-aromatic rings directly attached
to the left side and right side of the 1,2,4-triazolopyridines (TZP),
respectively, were found to be potent and selective inhibitors of
human 11β-hydroxysteroid dehydrogenase-type 1 (11β-HSD-1)
enzyme. 3-(1-(4-Chlorophenyl)Âcyclopropyl)-8-cyclopropyl-[1,2,4]ÂtriazoloÂ[4,3-<i>a</i>]Âpyridine (<b>9f</b>) was identified as a potent
inhibitor of the 11β-HSD-1 enzyme with reduced Pregnane-X receptor
(PXR) transactivation activity. The binding orientation of this TZP
series was revealed by X-ray crystallography structure studies
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 Potent Parenterally Administered Factor XIa Inhibitor with Hydroxyquinolin-2(1<i>H</i>)‑one as the P2′ Moiety
Structure–activity
relationship optimization of phenylalanine
P1′ and P2′ regions with a phenylimidazole core resulted
in a series of potent FXIa inhibitors. Introducing 4-hydroxyquinolin-2-one
as the P2′ group enhanced FXIa affinity and metabolic stability.
Incorporation of an <i>N</i>-methyl piperazine amide group
to replace the phenylalanine improved both FXIa potency and aqueous
solubility. Combination of the optimization led to the discovery of
FXIa inhibitor <b>13</b> with a FXIa <i>K</i><sub>i</sub> of 0.04 nM and an aPTT EC<sub>2<i>x</i></sub> of
1.0 ÎĽM. Dose-dependent efficacy (EC<sub>50</sub> of 0.53 ÎĽM)
was achieved in the rabbit ECAT model with minimal bleeding time prolongation
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
Discovery of a Hepatitis C Virus NS5B Replicase Palm Site Allosteric Inhibitor (BMS-929075) Advanced to Phase 1 Clinical Studies
The hepatitis C virus (HCV) NS5B
replicase is a prime target for
the development of direct-acting antiviral drugs for the treatment
of chronic HCV infection. Inspired by the overlay of bound structures
of three structurally distinct NS5B palm site allosteric inhibitors,
the high-throughput screening hit anthranilic acid <b>4</b>,
the known benzofuran analogue <b>5</b>, and the benzothiadiazine
derivative <b>6</b>, an optimization process utilizing the simple
benzofuran template <b>7</b> as a starting point for a fragment
growing approach was pursued. A delicate balance of molecular properties
achieved via disciplined lipophilicity changes was essential to achieve
both high affinity binding and a stringent targeted absorption, distribution,
metabolism, and excretion profile. These efforts led to the discovery
of BMS-929075 (<b>37</b>), which maintained ligand efficiency
relative to early leads, demonstrated efficacy in a triple combination
regimen in HCV replicon cells, and exhibited consistently high oral
bioavailability and pharmacokinetic parameters across preclinical
animal species. The human PK properties from the Phase I clinical
studies of <b>37</b> were better than anticipated and suggest
promising potential for QD administration
Discovery and Preclinical Characterization of the Cyclopropylindolobenzazepine BMS-791325, A Potent Allosteric Inhibitor of the Hepatitis C Virus NS5B Polymerase
Described herein are structure–activity
relationship studies
that resulted in the optimization of the activity of members of a
class of cyclopropyl-fused indolobenzazepine HCV NS5B polymerase inhibitors.
Subsequent iterations of analogue design and syntheses successfully
addressed off-target activities, most notably human pregnane X receptor
(hPXR) transactivation, and led to significant improvements in the
physicochemical properties of lead compounds. Those analogues exhibiting
improved solubility and membrane permeability were shown to have notably
enhanced pharmacokinetic profiles. Additionally, a series of alkyl
bridged piperazine carboxamides was identified as being of particular
interest, and from which the compound BMS-791325 (<b>2</b>)
was found to have distinguishing antiviral, safety, and pharmacokinetic
properties that resulted in its selection for clinical evaluation