6 research outputs found
Discovery of Novel P1 Groups for Coagulation Factor VIIa Inhibition Using Fragment-Based Screening
A multidisciplinary,
fragment-based screening approach involving
protein ensemble docking and biochemical and NMR assays is described.
This approach led to the discovery of several structurally diverse,
neutral surrogates for cationic factor VIIa P1 groups, which are generally
associated with poor pharmacokinetic (PK) properties. Among the novel
factor VIIa inhibitory fragments identified were aryl halides, lactams,
and heterocycles. Crystallographic structures for several bound fragments
were obtained, leading to the successful design of a potent factor
VIIa inhibitor with a neutral lactam P1 and improved permeability
Tetrahydroquinoline Derivatives as Potent and Selective Factor XIa Inhibitors
Antithrombotic
agents that are inhibitors of factor XIa (FXIa)
have the potential to demonstrate robust efficacy with a low bleeding
risk profile. Herein, we describe a series of tetrahydroquinoline
(THQ) derivatives as FXIa inhibitors. Compound <b>1</b> was
identified as a potent and selective tool compound for proof of concept
studies. It exhibited excellent antithrombotic efficacy in rabbit
thrombosis models and did not prolong bleeding times. This demonstrates
proof of concept for the FXIa mechanism in animal models with a reversible,
small molecule inhibitor
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
Phenylimidazoles as Potent and Selective Inhibitors of Coagulation Factor XIa with in Vivo Antithrombotic Activity
Novel inhibitors of FXIa containing
an (<i>S</i>)-2-phenyl-1-(4-phenyl-1<i>H</i>-imidazol-2-yl)Âethanamine
core have been optimized to provide
compound <b>16b</b>, a potent, reversible inhibitor of FXIa
(<i>K</i><sub>i</sub> = 0.3 nM) having in vivo antithrombotic
efficacy in the rabbit AV-shunt thrombosis model (ID<sub>50</sub> =
0.6 mg/kg + 1 mg kg<sup>–1</sup> h<sup>–1</sup>). Initial
analog selection was informed by molecular modeling using
compounds <b>11a</b> and <b>11h</b> overlaid onto the
X-ray crystal structure of tetrahydroquinoline <b>3</b> complexed
to FXIa. Further optimization was achieved by specific modifications
derived from careful analysis of the X-ray crystal structure of the
FXIa/<b>11h</b> complex. Compound <b>16b</b> was well
tolerated and enabled extensive pharmacologic evaluation of the FXIa
mechanism up to the ID<sub>90</sub> for thrombus inhibition
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 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