Delving into the Latest Updates on Narlaprevir with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Arlansa, Narlaprevir (USAN/INN)

Target

NS3/NS4A

Mechanism

NS3/NS4A inhibitors(Hepatitis C virus serine protease, NS3/NS4A inhibitors)

Therapeutic Areas

Infectious DiseasesDigestive System Disorders

Active Indication

Hepatitis C

Inactive Indication

Chronic hepatitis C genotype 1Hepatitis C, Chronic

Originator Organization

Merck & Co., Inc.

Active Organization

R-Pharm Group

Inactive Organization

Merck Sharp & Dohme Corp.Merck GmbH

Drug Highest PhaseApproved

First Approval Date

RU (03 Jun 2016),

Hepatitis C

Regulation-

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Structure

Molecular FormulaC36H61N5O7S

InChIKeyRICZEKWVNZFTNZ-LFGITCQGSA-N

CAS Registry865466-24-6

The study purpose is to evaluate the potential for a pharmacokinetic drug-drug interaction, safety and tolerability when Narlaprevir, Ritonavir (used as a metabolic inhibitor) and Tenofovir disoproxil fumarate (part 1) and Narlaprevir, Ritonavir and Raltegravir (part 2) are administered in combination to healthy volunteers.

Start Date24 Apr 2017

Sponsor / Collaborator

R-Pharm JSC

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100 Clinical Results associated with Narlaprevir

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100 Translational Medicine associated with Narlaprevir

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100 Patents (Medical) associated with Narlaprevir

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22

Literatures (Medical) associated with Narlaprevir

01 Sep 2023·Scientific African

The anti-SARS-CoV-2 activity of novel 9, 10-dihydrophenanthrene derivatives: an insight into molecular docking, ADMET analysis, and molecular dynamics simulation

Article

Author: Errougui, Abdelkbir ; Kouali, Mhammed El ; Abchir, Oussama ; Talbi, Mohammed ; Mali, Suraj N ; Chtita, Samir ; Yamari, Imane

Originating in Wuhan, the COVID-19 pandemic wave has had a profound impact on the global healthcare system. In this study, we used a 2D QSAR technique, ADMET analysis, molecular docking, and dynamic simulations to sort and evaluate the performance of thirty-nine bioactive analogues of 9,10-dihydrophenanthrene. The primary goal of the study is to use computational approaches to create a greater variety of structural references for the creation of more potent SARS-CoV-2 3Clpro inhibitors. This strategy is to speed up the process of finding active chemicals. Molecular descriptors were calculated using 'PaDEL' and 'ChemDes' software, and then redundant and non-significant descriptors were eliminated by a module in 'QSARINS ver. 2.2.2'. Subsequently, two statistically robust QSAR models were developed by applying multiple linear regression (MLR) methods. The correlation coefficients obtained by the two models are 0.89 and 0.82, respectively. These models were then subjected to internal and external validation tests, Y-randomization, and applicability domain analysis. The best model developed is applied to designate new molecules with good inhibitory activity values against severe acute respiratory syndrome coronavirus 2 (SARS CoV-2). We also examined various pharmacokinetic properties using ADMET analysis. Then, through molecular docking simulations, we used the crystal structure of the main protease of SARS-CoV-2 (3CLpro/Mpro) in a complex with the covalent inhibitor "Narlaprevir" (PDB ID: 7JYC). We also supported our molecular docking predictions with an extended molecular dynamics simulation of a docked ligand-protein complex. We hope that the results obtained in this study can be used as good anti-SARS-CoV-2 inhibitors.

28 Apr 2023·Pharmaceuticals (Basel, Switzerland)

Recent Advances in Covalent Drug Discovery.

Review

Author: Cheng, Xinlai ; Schaefer, Daniel

In spite of the increasing number of biologics license applications, the development of covalent inhibitors is still a growing field within drug discovery. The successful approval of some covalent protein kinase inhibitors, such as ibrutinib (BTK covalent inhibitor) and dacomitinib (EGFR covalent inhibitor), and the very recent discovery of covalent inhibitors for viral proteases, such as boceprevir, narlaprevir, and nirmatrelvir, represent a new milestone in covalent drug development. Generally, the formation of covalent bonds that target proteins can offer drugs diverse advantages in terms of target selectivity, drug resistance, and administration concentration. The most important factor for covalent inhibitors is the electrophile (warhead), which dictates selectivity, reactivity, and the type of protein binding (i.e., reversible or irreversible) and can be modified/optimized through rational designs. Furthermore, covalent inhibitors are becoming more and more common in proteolysis, targeting chimeras (PROTACs) for degrading proteins, including those that are currently considered to be 'undruggable'. The aim of this review is to highlight the current state of covalent inhibitor development, including a short historical overview and some examples of applications of PROTAC technologies and treatment of the SARS-CoV-2 virus.

13 Apr 2023·Briefings in Functional Genomics

A comprehensive protein design protocol to identify resistance mutations and signatures of adaptation in pathogens

Article

Author: Tripathi, Timir ; Padhi, Aditya K.

AbstractMost pathogens mutate and evolve over time to escape immune and drug pressure. To achieve this, they alter specific hotspot residues in their intracellular proteins to render the targeted drug(s) ineffective and develop resistance. Such hotspot residues may be located as a cluster or uniformly as a signature of adaptation in a protein. Identifying the hotspots and signatures is extremely important to comprehensively understand the disease pathogenesis and rapidly develop next-generation therapeutics. As experimental methods are time-consuming and often cumbersome, there is a need to develop efficient computational protocols and adequately utilize them. To address this issue, we present a unique computational protein design protocol that identifies hotspot residues, resistance mutations and signatures of adaptation in a pathogen’s protein against a bound drug. Using the protocol, the binding affinity between the designed mutants and drug is computed quickly, which offers predictions for comparison with biophysical experiments. The applicability and accuracy of the protocol are shown using case studies of a few protein–drug complexes. As a validation, resistance mutations in severe acute respiratory syndrome coronavirus 2 main protease (Mpro) against narlaprevir (an inhibitor of hepatitis C NS3/4A serine protease) are identified. Notably, a detailed methodology and description of the working principles of the protocol are presented. In conclusion, our protocol will assist in providing a first-hand explanation of adaptation, hotspot-residue variations and surveillance of evolving resistance mutations in a pathogenic protein.

100 Deals associated with Narlaprevir

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External Link

KEGG	Wiki	ATC	Drug Bank
D09644	Narlaprevir	J05AP	DB14760

R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Hepatitis C	RU	R-Pharm Group	03 Jun 2016

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Hepatitis C, Chronic	Phase 2	-	Merck Sharp & Dohme Corp.	20 Feb 2007
Hepatitis C	Phase 2	US	Merck GmbH	-
Chronic hepatitis C genotype 1	Discovery	-	Merck Sharp & Dohme Corp.	01 Jul 2007