13 research outputs found
Crystallization-Induced Dynamic Resolution toward the Synthesis of (<i>S</i>)‑7-Amino‑5<i>H</i>,7<i>H</i>‑dibenzo[<i>b</i>,<i>d</i>]‑azepin-6-one: An Important Scaffold for γ‑Secretase Inhibitors
An
enantioselective synthesis of (<i>S</i>)-7-amino-5<i>H</i>,7<i>H</i>-dibenzoÂ[<i>b</i>,<i>d</i>]Âazepin-6-one (<i>S</i>-<b>1</b>) is described.
The key step in the sequence involved crystallization-induced dynamic
resolution (CIDR) of compound <b>7</b> using Boc-d-phenylalanine
as a chiral resolving agent and 3,5-dichlorosalicylaldehyde as a racemization
catalyst to afford <i>S</i>-<b>1</b> in 81% overall
yield with 98.5% enantiomeric excess
Evolution of a Scale-Up Synthesis to a Potent GluN2B Inhibitor and Its Prodrug
This paper describes the efficient
scale-up synthesis of the potent
negative allosteric glutamate N2B (GluN2B) inhibitor <b>1</b> (BMS-986169), which relies upon a stereospecific S<sub>N</sub>2
alkylation strategy and a robust process for the preparation of its
phosphate prodrug <b>28</b> (BMS-986163) from parent <b>1</b> using POCl<sub>3</sub>. A deoxyfluorination reaction employing bisÂ(2-methoxyethyl)Âaminosulfur
trifluoride (Deoxo-Fluor) is also used to stereospecifically introduce
a fluorine substituent. The optimized routes have been demonstrated
to provide APIs suitable for toxicological studies in vivo
Discovery of Potent and Selective Quinoxaline-Based Protease-Activated Receptor 4 (PAR4) Antagonists for the Prevention of Arterial Thrombosis
PAR4
is a promising antithrombotic target with potential for separation
of efficacy from bleeding risk relative to current antiplatelet therapies.
In an effort to discover a novel PAR4 antagonist chemotype, a quinoxaline-based
HTS hit 3 with low μM potency was identified. Optimization
of the HTS hit through the use of positional SAR scanning and the
design of conformationally constrained cores led to the discovery
of a quinoxaline-benzothiazole series as potent and selective PAR4
antagonists. The lead compound 48, possessing a 2 nM
IC50 against PAR4 activation by γ-thrombin in platelet-rich
plasma (PRP) and greater than 2500-fold selectivity versus PAR1, demonstrated
robust antithrombotic efficacy and minimal bleeding in the cynomolgus
monkey models
Discovery of BMS-641988, a Novel Androgen Receptor Antagonist for the Treatment of Prostate Cancer
BMS-641988 (<b>23</b>) is a
novel, nonsteroidal androgen
receptor antagonist designed for the treatment of prostate cancer.
The compound has high binding affinity for the AR and acts as a functional
antagonist <i>in vitro</i>. BMS-641988 is efficacious in
multiple human prostate cancer xenograft models, including CWR22-BMSLD1
where it displays superior efficacy relative to bicalutamide. Based
on its promising preclinical profile, BMS-641988 was selected for
clinical development
Discovery of Potent and Selective Quinoxaline-Based Protease-Activated Receptor 4 (PAR4) Antagonists for the Prevention of Arterial Thrombosis
PAR4
is a promising antithrombotic target with potential for separation
of efficacy from bleeding risk relative to current antiplatelet therapies.
In an effort to discover a novel PAR4 antagonist chemotype, a quinoxaline-based
HTS hit 3 with low μM potency was identified. Optimization
of the HTS hit through the use of positional SAR scanning and the
design of conformationally constrained cores led to the discovery
of a quinoxaline-benzothiazole series as potent and selective PAR4
antagonists. The lead compound 48, possessing a 2 nM
IC50 against PAR4 activation by γ-thrombin in platelet-rich
plasma (PRP) and greater than 2500-fold selectivity versus PAR1, demonstrated
robust antithrombotic efficacy and minimal bleeding in the cynomolgus
monkey models
The Discovery of GSK3640254, a Next-Generation Inhibitor of HIV‑1 Maturation
GSK3640254 is an HIV-1 maturation inhibitor (MI) that
exhibits
significantly improved antiviral activity toward a range of clinically
relevant polymorphic variants with reduced sensitivity toward the
second-generation MI GSK3532795 (BMS-955176). The key structural difference
between GSK3640254 and its predecessor is the replacement of the para-substituted benzoic acid moiety attached at the C-3
position of the triterpenoid core with a cyclohex-3-ene-1-carboxylic
acid substituted with a CH2F moiety at the carbon atom
α- to the pharmacophoric carboxylic acid. This structural element
provided a new vector with which to explore structure–activity
relationships (SARs) and led to compounds with improved polymorphic
coverage while preserving pharmacokinetic (PK) properties. The approach
to the design of GSK3640254, the development of a synthetic route
and its preclinical profile are discussed. GSK3640254 is currently
in phase IIb clinical trials after demonstrating a dose-related reduction
in HIV-1 viral load over 7–10 days of dosing to HIV-1-infected
subjects
The Discovery of GSK3640254, a Next-Generation Inhibitor of HIV‑1 Maturation
GSK3640254 is an HIV-1 maturation inhibitor (MI) that
exhibits
significantly improved antiviral activity toward a range of clinically
relevant polymorphic variants with reduced sensitivity toward the
second-generation MI GSK3532795 (BMS-955176). The key structural difference
between GSK3640254 and its predecessor is the replacement of the para-substituted benzoic acid moiety attached at the C-3
position of the triterpenoid core with a cyclohex-3-ene-1-carboxylic
acid substituted with a CH2F moiety at the carbon atom
α- to the pharmacophoric carboxylic acid. This structural element
provided a new vector with which to explore structure–activity
relationships (SARs) and led to compounds with improved polymorphic
coverage while preserving pharmacokinetic (PK) properties. The approach
to the design of GSK3640254, the development of a synthetic route
and its preclinical profile are discussed. GSK3640254 is currently
in phase IIb clinical trials after demonstrating a dose-related reduction
in HIV-1 viral load over 7–10 days of dosing to HIV-1-infected
subjects
Discovery of Clinical Candidate BMS-906024: A Potent Pan-Notch Inhibitor for the Treatment of Leukemia and Solid Tumors
Structure–activity relationships
in a series of (2-oxo-1,4-benzodiazepin-3-yl)-succinamides
identified highly potent inhibitors of γ-secretase mediated
signaling of Notch1/2/3/4 receptors. On the basis of its robust in
vivo efficacy at tolerated doses in Notch driven leukemia and solid
tumor xenograft models, <b>12</b> (BMS-906024) was selected
as a candidate for clinical evaluation
Selective <i>I</i><sub>Kur</sub> Inhibitors for the Potential Treatment of Atrial Fibrillation: Optimization of the Phenyl Quinazoline Series Leading to Clinical Candidate 5‑[5-Phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridine-3-sulfonamide
We
have recently disclosed 5-phenyl-<i>N</i>-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)Âquinazolin-4-amine <b>1</b> as a potent <i>I</i><sub>Kur</sub> current blocker
with selectivity versus <i>h</i>ERG, Na and Ca channels,
and an acceptable preclinical PK profile. Upon further characterization <i>in vivo</i>, compound <b>1</b> demonstrated an unacceptable
level of brain penetration. In an effort to reduce the level of brain
penetration while maintaining the overall profile, SAR was developed
at the C2′ position for a series of close analogues by employing
hydrogen bond donors. As a result, 5-[5-phenyl-4-(pyridin-2-ylmethylamino)Âquinazolin-2-yl]Âpyridine-3-sulfonamide
(<b>25</b>) was identified as the lead compound in this series.
Compound <b>25</b> showed robust effects in rabbit and canine
pharmacodynamic models and an acceptable cross-species pharmacokinetic
profile and was advanced as the clinical candidate. Further optimization
of <b>25</b> to mitigate pH-dependent absorption resulted in
identification of the corresponding phosphoramide prodrug (<b>29</b>) with an improved solubility and pharmacokinetic profile
Triphenylethanamine Derivatives as Cholesteryl Ester Transfer Protein Inhibitors: Discovery of <i>N</i>‑[(1<i>R</i>)‑1-(3-Cyclopropoxy-4-fluorophenyl)-1-[3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)Âphenyl]-2-phenylethyl]-4-fluoro-3-(trifluoromethyl)Âbenzamide (BMS-795311)
Cholesteryl ester transfer protein
(CETP) inhibitors raise HDL-C
in animals and humans and may be antiatherosclerotic by enhancing
reverse cholesterol transport (RCT). In this article, we describe
the lead optimization efforts resulting in the discovery of a series
of triphenylethanamine (TPE) ureas and amides as potent and orally
available CETP inhibitors. Compound <b>10g</b> is a potent CETP
inhibitor that maximally inhibited cholesteryl ester (CE) transfer
activity at an oral dose of 1 mg/kg in human CETP/apoB-100 dual transgenic
mice and increased HDL cholesterol content and size comparable to
torcetrapib (<b>1</b>) in moderately-fat fed hamsters. In contrast
to the off-target liabilities with <b>1</b>, no blood pressure
increase was observed with <b>10g</b> in rat telemetry studies
and no increase of aldosterone synthase (CYP11B2) was detected in
H295R cells. On the basis of its preclinical profile, compound <b>10g</b> was advanced into preclinical safety studies