9 research outputs found
Pharmacokinetics, Metabolism, and Partial Biodistribution of âPincer Therapeuticâ Nitazoxanide in Mice following Pulmonary Delivery of Inhalable Particles
Nitazoxanide (NTZ) induces autophagy
in mammalian cells and also
has mycobactericidal activity, displaying a two-pronged therapeutic
effect, on the host as well as the pathogen. The pharmacokinetics
and biodistribution of inhaled NTZ were investigated. Particles containing
NTZ in a matrix of PLGA were prepared by spray drying. HPLC and LCâMS/MS
methods were developed and validated. Particles were administered
as inhalations to mice. Drug concentrations in plasma and tissues
were estimated at different time points. Drug loading (âŒ36%),
entrapment efficiency (>90%), and the conversion of NTZ into metabolites
in plasma and lung homogenates were assessed satisfactorily by HPLC.
NTZ pharmacokinetics and biodistribution following intravenous administration
or inhalation were established by LCâMS. NTZ converted into
tizoxanide (99% in 30 min) and other metabolites. Pulmonary delivery
of NTZ entrapped in particles increased the half-life of the drug
by factors of 3, 12, and 200 in the plasma, lung tissue, and alveolar
macrophages, respectively. Targeted delivery and prolonged lung retention
along with dose sparing of the kidneys was observed upon pulmonary
delivery as compared to intravenous administration
Crystallization-Induced Dynamic Resolution toward the Synthesis of (<i>S</i>)â7-Aminoâ5<i>H</i>,7<i>H</i>âdibenzo[<i>b</i>,<i>d</i>]âazepin-6-one: An Important Scaffold for ÎłâSecretase 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
Nanocarrier Composed of Magnetite Core Coated with Three Polymeric Shells Mediates LCSâ1 Delivery for Synthetic Lethal Therapy of BLM-Defective Colorectal Cancer Cells
Synthetic
lethality is a molecular-targeted therapy for selective
killing of cancer cells. We exploited a lethal interaction between
superoxide dismutase 1 inhibition and Bloom syndrome gene product
(BLM) defect for the treatment of colorectal cancer (CRC) cells (HCT
116) with a customized lung cancer screen-1-loaded nanocarrier (LCS-1-NC).
The drug LCS-1 has poor aqueous solubility. To overcome its limitations,
a customized NC, composed of a magnetite core coated with three polymeric
shells, namely, aminocellulose (AC), branched polyÂ(amidoamine), and
paraben-PEG, was developed for encapsulating LCS-1. Encapsulation
efficiency and drug loading were found to be 74% and 8.2%, respectively.
LCS-1-NC exhibited sustained release, with âŒ85% of drug release
in 24 h. Blank NC (0.5 mg/mL) exhibited cytocompatibility toward normal
cells, mainly due to the AC layer. LCS-1-NC demonstrated high killing
selectivity (104 times) toward BLM-deficient HCT 116 cells over BLM-proficient
HCT 116 cells. Due to enhanced efficacy of the drug using NC, the
sensitivity difference for BLM-deficient cells increased to 1.7 times
in comparison to that with free LCS-1. LCS-1-NC induced persistent
DNA damage and apoptosis, which demonstrates that LCS-1-NC effectively
and preferentially killed BLM-deficient CRC cells. This is the first
report on the development of a potential drug carrier to improve the
therapeutic efficacy of LCS-1 for specific killing of CRC cells having
BLM defects
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
The Discovery of GSK3640254, a Next-Generation Inhibitor of HIVâ1 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 structureâactivity
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 7â10 days of dosing to HIV-1-infected
subjects
The Discovery of GSK3640254, a Next-Generation Inhibitor of HIVâ1 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 structureâactivity
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 7â10 days of dosing to HIV-1-infected
subjects
Discovery of a Highly Selective JAK2 Inhibitor, BMS-911543, for the Treatment of Myeloproliferative Neoplasms
JAK2 kinase inhibitors are a promising
new class of agents for
the treatment of myeloproliferative neoplasms and have potential for
the treatment of other diseases possessing a deregulated JAK2-STAT
pathway. X-ray structure and ADME guided refinement of C-4 heterocycles
to address metabolic liability present in dialkylthiazole <b>1</b> led to the discovery of a clinical candidate, BMS-911543 (<b>11</b>), with excellent kinome selectivity, <i>in vivo</i> PD activity, and safety profile