PROTACs: Current Trends in Protein Degradation by Proteolysis-Targeting Chimeras.

In the recent past, proteolysis-targeting chimera (PROTAC) technology has received enormous attention for its ability to overcome the limitations of protein inhibitors and its capability to target undruggable proteins. The PROTAC molecule consists of three components, a ubiquitin E3 ligase ligand, a linker, and a target protein ligand. The application of this technology is rapidly gaining momentum, especially in cancer therapy.

Exploration of the Plausible Mechanism of Ethambutol Induced Ocular Toxicity by Using Proteomics Informed Physiologically Based Pharmacokinetic (PBPK) Modeling.

Purpose: Ethambutol (EMB) is a first-line anti-tubercular drug that is known to cause optic neuropathy. The exact mechanism of its eye toxicity is unknown; however, proposition is metal chelating effect of both EMB and its metabolite 2,2'-(ethylenediamino)-dibutyric acid (EDBA). The latter is formed by sequential metabolism of EMB by alcohol dehydrogenases (ADHs) and aldehyde dehydrogenases (ALDHs).

Exploration of inhibition potential of isoniazid and its metabolites towards CYP2E1 in human liver microsomes through LC-MS/MS analysis.

Isoniazid (INH) is the first-line anti-tubercular drug that is used both for the prophylaxis as well as the treatment of tuberculosis (TB). The patients with TB are more vulnerable to secondary infections and other health complications, hence, they are usually administered a cocktail of drugs. This increases the likelihood of drug-drug interactions (DDIs).

Discovery of CA-4948, an Orally Bioavailable IRAK4 Inhibitor for Treatment of Hematologic Malignancies.

Small molecule potent IRAK4 inhibitors from a novel bicyclic heterocycle class were designed and synthesized based on hits identified from Aurigene's compound library. The advanced lead compound, CA-4948, demonstrated good cellular activity in ABC DLBCL and AML cell lines. Inhibition of TLR signaling leading to decreased IL-6 levels was also observed in whole blood assays.

Insights into the degradation chemistry of tazarotene, a third generation acetylenic retinoid: LC-HRMS (Orbitrap), LC-MS and NMR characterization of its degradation products, and prediction of their physicochemical and ADMET properties.

Tazarotene is a prodrug that belongs to the acetylenic class of retinoids. The drug was subjected to hydrolytic, oxidative and photolytic stress testing to establish its comprehensive degradation chemistry. The drug proved to be unstable under acidic and basic hydrolytic conditions, yielding tazarotenic acid, which is a known major degradation product (DP) and an active metabolite.

In vitro evaluation of reactive nature of E- and Z-guggulsterones and their metabolites in human liver microsomes using UHPLC-Orbitrap mass spectrometer.

Guggulipid is known to be useful for hypercholesterolemia, arthritis, acne, and obesity. These activities are attributed to its two principal isomeric active constituents, viz., E- and Z-guggulsterones.

Characterization of Photodegradation Products of Bepotastine Besilate and In Silico Evaluation of Their Physicochemical, Absorption, Distribution, Metabolism, Excretion and Toxicity Properties.

Bepotastine (BPT) is a H-receptor antagonist. It is used as a besilate salt in ophthalmic solution for allergic conjunctivitis and orally for the treatment of allergic rhinitis and urticaria/pruritus. Its systematic forced degradation study is unreported.

Characterization of stable and reactive metabolites of piperine formed on incubation with human liver microsomes.

Black pepper, though commonly employed as a spice, has many medicinal properties. It consists of volatile oils, alkaloids, pungent resins, etc., of which piperine is a major constituent.

Stability behaviour of antiretroviral drugs and their combinations. 10: LC-HRMS, LC-MS, LC-NMR and NMR characterization of fosamprenavir degradation products and in silico determination of their ADMET properties.

The present study focused upon the forced degradation behaviour of fosamprenavir (FPV), an antiretroviral drug. A total of six degradation products (DPs) were separated on a non-polar stationary phase by high performance liquid chromatography (HPLC). For the characterization, comprehensive mass fragmentation pathway of the drug was initially established using high resolution mass spectrometry (HRMS) and multi-stage tandem mass spectrometry (MS) data.

Novel Bruton tyrosine kinase inhibitor acalabrutinib quantification by validated LC-MS/MS method: An application to pharmacokinetic study in Sprague Dawley rats.

USFDA has approved a novel Bruton tyrosine kinase (BTK) inhibitor acalabrutinib (ACA) for the treatment of mantle cell lymphoma in adults. ACA is more potent and selective with fewer side effects compared to other Bruton tyrosine kinase inhibitors. In the current work a highly sensitive, selective and specific LC-MS/MS method for the estimation of acalabrutinib (ACA) in rat plasma was developed.

Evaluation of Herb-Drug Interaction of Synacinn™ and Individual Biomarker through Cytochrome 450 Inhibition Assay.

Background: SynacinnTM contains five standardized herbal extracts of Orthosiphon Stamineus (OS), Syzygium polyanthum (SZ), Curcuma xantorrizza (CX), Cinnamomum zeylanicum (CZ) and Andrographis paniculata (AP) and is standardized against phytochemical markers of rosmarinic acid, gallic acid, curcumin, catechin and andrographolide respectively. This herbal medicine has been used as health supplement for diabetes. SynacinnTM is recommended to be consumed as supplement to the diabetic drugs.

A validated LC-MS/MS method for the estimation of glimepiride and pitavastatin in rat plasma: Application to drug interaction studies.

Glimepiride (GLI) is prescribed for the management of type-2 diabetes where as pitavastatin (PIT) for the treatment of diabetes associated dyslipidemia. Both the drugs are metabolized by CYP2C9 and have the potential of altering the enzyme through either inhibition or induction. In this respect, we present a simple, fast and validated bioanalytical LC-MS/MS method for the simultaneous estimation of GLI and PIT from rat plasma.

Development and validation of a liquid chromatography-tandem mass spectrometry method for quantitation of indomethacin in rat plasma and its application to a pharmacokinetic study in rats.

A highly sensitive and rapid bioanalytical method has been developed and validated for the estimation of indomethacin in rat plasma with liquid chromatography coupled to tandem mass spectrometry with electrospray ionization in the positive-ion mode. The assay procedure involves a simple liquid-liquid extraction of indomethacin and phenacetin (internal standard, IS) from rat plasma with acetonitrile. Chromatographic separation was achieved with 0.

LC-MS/MS-ESI method for simultaneous quantitation of metformin and repaglinidie in rat plasma and its application to pharmacokinetic study in rats.

A highly sensitive and specific LC-MS/MS-ESI method has been developed for simultaneous quantification of metformin (MFN) and repaglinide (RGN) in rat plasma (50 μL) using phenacetin as an internal standard (IS). Simple protein precipitation was used to extract MFN and RGN from rat plasma. The chromatographic resolution of MFN, RGN and IS was achieved with a mobile phase consisting of 0.

Development and validation of a highly sensitive LC-MS/MS-ESI method for the determination of bicalutamide in mouse plasma: application to a pharmacokinetic study.

A highly sensitive, rapid assay method has been developed and validated for the estimation of bicalutamide in mouse plasma using liquid chromatography coupled to tandem mass spectrometry with electrospray ionization in the negative-ion mode. The assay procedure involves extraction of bicalutamide and tolbutamide (internal standard, IS) from mouse plasma with a simple protein precipitation method. Chromatographic separation was achieved using an isocratic mobile phase (0.

Development and validation of a highly sensitive LC-MS/MS-ESI method for the determination of nobiletin in rat plasma: application to a pharmacokinetic study.

A highly sensitive, rapid assay method has been developed and validated for the estimation of nobiletin in rat plasma with liquid chromatography coupled to tandem mass spectrometry with electrospray ionization in the positive-ion mode. The assay procedure involves extraction of nobiletin and citalopram (internal standard, IS) from rat plasma with liquid-liquid extraction. Chromatographic separation was achieved using an isocratic mobile phase (0.

Development and validation of an LC-MS/MS-ESI method for the determination of lorglumide, a CCK-1 antagonist in mouse plasma: application to a pharmacokinetic study.

A highly sensitive, rapid assay method was developed and validated for the estimation of lorglumide in mouse plasma using liquid chromatography coupled to tandem mass spectrometry with electrospray ionization in positive-ion mode. The assay procedure involves extraction of lorglumide and phenacetin (internal standard, IS) from mouse plasma with simple protein precipitation. Chromatographic separation was achieved using an isocratic mobile (0.

A strategy for extending the applicability of a validated plasma calibration curve to quantitative measurements in multiple tissue homogenate samples: a case study from a rat tissue distribution study of JI-101, a triple kinase inhibitor.

A general practice in bioanalysis is that, whatever the biological matrix the analyte is being quantified in, the validation is performed in the same matrix as per regulatory guidelines. In this paper, we are presenting the applicability of a validated LC-MS/MS method in rat plasma for JI-101, to estimate the concentrations of JI-101 in various tissues that were harvested in a rat tissue distribution study. A simple protein precipitation technique was used to extract JI-101 and internal standard from the tissue homogenates.

Highly sensitive LC-MS/MS-ESI method for simultaneous quantitation of albendazole and ricobendazole in rat plasma and its application to a rat pharmacokinetic study.

A highly sensitive and specific LC-MS/MS-ESI method was developed for simultaneous quantification of albenadazole (ABZ) and ricobendazole (RBZ) in rat plasma (50 μL) using phenacetin as an internal standard (IS). Simple protein precipitation was used to extract ABZ and RBZ from rat plasma. The chromatographic resolution of ABZ, RBZ and IS was achieved with a mobile phase consisting of 5 m m ammonium acetate (pH 6) and acetonitrile (20:80, v/v) at a flow rate of 1 mL/min on a Chromolith RP-18e column.

Highly sensitive method for the determination of adenosine by LC-MS/MS-ESI: method validation and scope of application to a pharmacokinetic/pharmacodynamic study.

A highly sensitive, rapid assay method has been developed and validated for the estimation of adenosine in rat plasma with liquid chromatography coupled to tandem mass spectrometry with electro-spray ionization in the positive-ion mode. The assay procedure involves extraction of adenosine and phenacetin (internal standard, IS) from rat plasma with a simple protein precipitation extraction process. The method was validated using rat plasma with extinguished adenosine endogenous levels.

Development and validation of a highly sensitive LC-MS/MS method for simultaneous quantitation of acetyl-CoA and malonyl-CoA in animal tissues.

A highly sensitive and specific LC-MS/MS method was developed for simultaneous estimation of acetyl co-enzyme A (ACoA) and malonyl co-enzyme A (MCoA) in surrogate matrix using n-propionyl co-enzyme A as an internal standard (IS). LC-MS/MS was operated under the multiple reaction-monitoring mode using the electrospray ionization technique. Simple acidification followed by dilution using an assay buffer process was used to extract ACoA, MCoA and IS from surrogate matrix and tissue samples.

LC-MS/MS-ESI method for simultaneous quantitation of three endocannabinoids and its application to rat pharmacokinetic studies.

An LC-MS/MS-ESI method has been validated for simultaneous estimation of the three endocannabinoids; N-arachidonoylethanolamine (AEA), N-oleoylethanolamine (OEA) and palmitoylethanolamide (PEA), in surrogate matrix using AEA-d (4) as an internal standard with highest sensitivity over the existing methods. Simple precipitation was used to extract analytes and these were subsequently analyzed on a monolithic column. Linear response function was established over the concentration range 12.

A highly sensitive LC-MS/MS method for the determination of S-raclopride in rat plasma: application to a pharmacokinetic study in rats.

A highly sensitive and rapid assay method has been developed and validated for the estimation of S-(-)-raclopride (S-RCP) in rat plasma with liquid chromatography coupled to tandem mass spectrometry with electrospray ionization in the positive ion mode. The assay procedure involves a simple liquid-liquid extraction technique for extraction of S-RCP and phenacetin (internal standard, IS) from rat plasma. Chromatographic separation was achieved with 0.

Highly sensitive method for the determination of a novel triple kinase inhibitor with anti-cancer activity, JI-101, in rat plasma by liquid chromatography-electrospray ionization tandem mass spectrometry: application to a pharmacokinetic study.

A highly sensitive, rapid assay method has been developed and validated for the estimation of JI-101 in rat plasma with liquid chromatography coupled to tandem mass spectrometry with electrospray ionization in the positive-ion mode. The assay procedure involves extraction of JI-101 and phenacetin (internal standard, IS) from rat plasma with a solid-phase extraction process. Chromatographic separation was achieved using a binary gradient using mobile phase A (acetonitrile) and B (0.

A highly sensitive LC-MS/MS method for the determination of S-citalopram in rat plasma: application to a pharmacokinetic study in rats.

A highly sensitive, rapid assay method has been developed and validated for the estimation of S-citalopram (S-CPM) in rat plasma with liquid chromatography coupled to tandem mass spectrometry with electrospray ionization in the positive-ion mode. The assay procedure involves a simple liquid-liquid extraction of S-CPM and phenacetin (internal standard, IS) from rat plasma with t-butyl methyl ether. Chromatographic separation was operated with 0.