Rescriptor (delavirdine mesylate) / ViiV Healthcare - LARVOL DELTA

Delavirdine modifies action potential configuration via inhibition of IKr and Ito in canine ventricular myocytes. (PubMed, Biomed Pharmacother) - "Delavirdine is an anti-HIV agent with structural similarity (presence of methanesulfonamide group) to well-known rapid delayed rectifier potassium current (IKr) inhibitors like dofetilide and E-4031. These results support the delavirdine-evoked inhibition of IKr, transient outward potassium current as well as sodium current. As these concentrations are similar to therapeutic plasma values (7-30 µM), delavirdine application might carry some risk of cardiac side effects especially in HIV-infected patients with altered cardiac function or patients with co-administration of drugs metabolized by certain cytochrome P450 isoforms."

Journal • Cardiovascular • Human Immunodeficiency Virus • Infectious Disease • NAV1

Recent report on indoles as a privileged anti-viral scaffold in drug discovery. (PubMed, Eur J Med Chem) - "Indole-containing drugs, such as enfuvirtide (T-20), arbidol, and delavirdine, have demonstrated significant efficacy in treating viral diseases. The review includes discussions on synthetic protocols, inhibitory concentrations, SAR study, and computational study. This review shall identify new antiviral indoles that may help to combat new viral threats in the future."

Journal • Review • Dengue Fever • Ebola Virus Disease • Hepatology • Human Immunodeficiency Virus • Infectious Disease • Inflammation • Influenza • Novel Coronavirus Disease • Respiratory Diseases

Design, Synthesis, Biological Evaluation and Molecular Docking Studies of New Thiazolidinone Derivatives as NNRTIs and SARS-CoV-2 Main Protease Inhibitors. (PubMed, Chem Biodivers) - "FDA approved Delavirdine bearing a sulfonamide moiety, while thiazolidinone has demonstrated significant anti-HIV activity as a core heterocycle or derivative of substituted heterocycles...Seven compounds showed good anti-HIV inhibitory activity, with two of them, C1 and C2 being better (IC50 0.18 μΜ & 0.12 μΜ respectively) than the reference drug nevirapine (IC50 0.31 μΜ). The evaluation of molecules to inhibit the main protease revealed that 6 of the synthesized compounds exhibited excellent to moderate activity with two of them (B4 and B10) having better IC50 values (0.15 & 0.19 μΜ respectively) than the reference inhibitor GC376 (IC50 0.439 μΜ). The docking studies is coincides with experimental results, showing good binding mode to both enzymes."

Journal • Human Immunodeficiency Virus • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Identification and characterization of domain-specific inhibitors of DENV NS3 and NS5 proteins by in silico screening methods. (PubMed, J Biomol Struct Dyn) - "Our comprehensive analysis identified tolcapone, cefprozil, delavirdine and indinavir as potential inhibitors of NS5 MTase, NS5 RdRp, NS3 protease and NS3 helicase functions, respectively. These high-confidence candidate molecules will be useful for developing effective anti-DENV therapy to combat dengue infection.Communicated by Ramaswamy H. Sarma."

Journal • Dengue Fever • Infectious Disease

Current insights and molecular docking studies of HIV-1 reverse transcriptase inhibitors. (PubMed, Chem Biol Drug Des) - "Zidovudine, didanosine, and stavudine are FDA-approved NRTIs, while nevirapine, efavirenz, and delavirdine are FDA-approved NNRTIs. Several agents are in clinical trials, including apricitabine, racivir, elvucitabine, doravirine, dapivirine, and elsulfavirine. This review addresses HIV-1 structure, replication cycle, reverse transcription, and HIV drug targets. This study focuses on NRTIs and NNRTIs, their binding sites, mechanisms of action, FDA-approved drugs and drugs in clinical trials, their resistance and adverse effects, their molecular docking studies, and highly active antiretroviral therapy (HAART)."

Journal • Review • Human Immunodeficiency Virus • Infectious Disease

Drug repurposing of FDA-approved anti-viral drugs via computational screening against novel 6M03 SARS-COVID-19. (PubMed, Ir J Med Sci) - "In our study, we also observed the nucleotide sequence of protease protein consisting of 316 amino acid residues and the influence of these pronouncing drugs over these sequences. The outcome of this research work provides researchers with a track record for carrying out further investigational procedures by applying docking simulations and in vitro and in vivo experimentation with these reprofile drugs so that a better drug can be formulated against coronavirus."

FDA event • Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Hybrids of delavirdine and piperdin-4-yl-aminopyrimidines (DPAPYs) as potent HIV-1 NNRTIs: Design, synthesis and biological activities. (PubMed, Eur J Med Chem) - "Gratifyingly, it exhibited good to excellent potency against the single HIV-1 mutants L100I, K103N, Y181C, Y188L, E138K, as well as the double mutant F227L + V106A. Furthermore, the preliminary structure-activity relationships were summarized, molecular modeling was conducted to explore the binding mode of DPAPYs and HIV-1 RT, and their physicochemical properties were also predicted."

Journal • Human Immunodeficiency Virus • Infectious Disease

In silico design, synthesis and anti-HIV activity of quinoline derivatives as non-nucleoside reverse transcriptase inhibitors (NNRTIs). (PubMed, Comput Biol Chem) - "Further, molecular dynamics (MD) simulations were performed on compound 6 and delavirdine with HIV-RT enzyme...Thus, the compound 6 might act as a potential inhibitor against HIV-RT. Overall, this study revealed that compound 6 (5-hydroxy-N-(4-methyl-2-oxo-1,2-dihydroquinolin-8-yl) thiophene-2-sulfonamide) has prudent anti-HIV activity against both HIV-1 (SI = 2.65) and HIV-2 (SI = 2.32) that can further be utilised in drug discovery against HIV virus."

Journal • Human Immunodeficiency Virus • Infectious Disease

Effect of CYP3A4 Inhibitors and Inducers on Pharmacokinetics and Pharmacodynamics of Saxagliptin and Active Metabolite M2 in Humans Using Physiological-Based Pharmacokinetic Combined DPP-4 Occupancy. (PubMed, Front Pharmacol) - "The prediction results demonstrated that the oral dose of saxagliptin should be reduced to 2.5 mg when coadministrated with ketoconazole. The predictions also showed that although PK profiles of saxagliptin showed significant changes with delavirdine (AUC 1.5-fold increase) or rifampicin (AUC: a decrease to 0.19-fold) compared to those without inhibitors or inducers, occupancies of DPP-4 by saxagliptin were nearly unchanged, that is, the administration dose of saxagliptin need not adjust when there is coadministration with delavirdine or rifampicin."

Journal • PK/PD data

The Expanding Role of Pyridine and Dihydropyridine Scaffolds in Drug Design. (PubMed, Drug Des Devel Ther) - "In the US FDA database, there are 95 approved pharmaceuticals that stem from pyridine or dihydropyridine, including isoniazid and ethionamide (tuberculosis), delavirdine (HIV/AIDS), abiraterone acetate (prostate cancer), tacrine (Alzheimer's), ciclopirox (ringworm and athlete's foot), crizotinib (cancer), nifedipine (Raynaud's syndrome and premature birth), piroxicam (NSAID for arthritis), nilvadipine (hypertension), roflumilast (COPD), pyridostigmine (myasthenia gravis), and many more. This review examines the prospects of highly potent bioactive molecules to emphasize the advantages of using pyridine and dihydropyridine in drug design. We cover the most recent developments from 2010 to date, highlighting the ever-expanding role of both scaffolds in the field of medicinal chemistry and drug development."

Journal • Review • Alzheimer's Disease • Cardiovascular • Chronic Obstructive Pulmonary Disease • CNS Disorders • Genito-urinary Cancer • Human Immunodeficiency Virus • Hypertension • Immunology • Infectious Disease • Myasthenia Gravis • Oncology • Prostate Cancer • Pulmonary Disease • Respiratory Diseases • Rheumatology • Solid Tumor • Tuberculosis

Therapeutic potential of indole derivatives as anti-HIV agents: A mini-review. (PubMed, Curr Top Med Chem) - "Indole derivatives are potential inhibitors of HIV enzymes such as reverse transcriptase, integrase and protease, and some indole-based agents like Delavirdine have already been applied in clinics or under clinical evaluations for the treatment of AIDS/HIV, revealing that indole moiety is a useful template for the development of anti-HIV agents. This review focuses on the recent advancement of indole derivatives including indole alkaloids, hybrids, and dimers with anti-HIV potential, covering articles published between 2010 and 2020. The chemical structures, structure-activity relationship and mechanisms of action are also discussed."

Journal • Review • Human Immunodeficiency Virus • Immunology • Infectious Disease

Using Integrated Computational Approaches to Identify Safe and Rapid Treatment for SARS -CoV- 2. (PubMed, J Biomol Struct Dyn) - "The current study provides a powerful in silico results, means for rapid screening of drugs as anti-protease medications and recommend that the above-mentioned drugs can be used in the treatment of SARS-CoV-2 in combined or sole therapy."

Journal • Novel Coronavirus Disease

Development of non-nucleoside reverse transcriptase inhibitors (NNRTIs): our past twenty years. (PubMed, Acta Pharm Sin B) - "In this paper, we review the development of NNRTIs in the last two decades using the above optimization strategies, including their structure-activity relationships, molecular modeling, and their binding modes with HIV-1 reverse transcriptase (RT). Future directions and perspectives on the design and associated challenges are also discussed."

Journal • Review • Gene Therapies • Human Immunodeficiency Virus • Immunology • Infectious Disease • Targeted Protein Degradation

Challenges and approaches in the discovery of human immunodeficiency virus type-1 non-nucleoside reverse transcriptase inhibitors. (PubMed, Med Res Rev) - "At present, there are six nonnucleoside reverse transcriptase inhibitors (NNRTIs) approved for clinical use: nevirapine (NVP), delavirdine (DLV), efavirenz (EFV), etravirine (ETV), rilpivirine (RPV), and elsulfavirine. We will give an overview of traditional medicinal chemistry strategies for structural modification as bioisosterism principles, scaffold hopping, substitute decoration, and molecular hybridization. Furthermore, computer-aid design as virtual screening, de novo design and free-energy perturbation will be described in details."

Journal • Review • Gene Therapies • Human Immunodeficiency Virus • Immunology • Infectious Disease

Application of Molecular Docking for the Development of Improved HIV-1 Reverse Transcriptase Inhibitors. (PubMed, Curr Comput Aided Drug Des) - "Binding energy improvement was higher for the structures designed based on second-generation NNRTIs (etravirine and rilpivirine) than the first-generation NNRTIs (delavirdine and efavirenz). For example, while the docked energy for rilpivirine was -51 KJ/mol, it was improved for its derivatives RPV01 and RPV15 up to -58.3 and -54.5 KJ/mol, respectively."

Journal • Gene Therapies • Human Immunodeficiency Virus • Immunology • Infectious Disease

The journey of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) from lab to clinic. (PubMed, J Med Chem) - "Among them, six NNRTIs were approved for HIV-1 treatment, namely, nevirapine (NVP), delavirdine (DLV), efavirenz (EFV), etravirine (ETR), rilpivirine (RPV), and doravirine (DOR). In this perspective, we focus on the six NNRTIs and lessons learned from their journey through development to clinical studies. It demonstrates the obligatory need of understanding the physicochemical and biological principles (lead optimization), resistance mutations, synthesis and clinical requirements for drugs."

Journal • Gene Therapies • Genetic Disorders • Human Immunodeficiency Virus • Immunology • Infectious Disease

Current and emerging non-nucleoside reverse transcriptase inhibitors (NNRTIs) for HIV-1 treatment. (PubMed, Expert Opin Drug Metab Toxicol) - "Expert opinion: Since the first NNRTI, nevirapine, was approved in 1996, antiviral drug discovery led to the approval of seven NNRTIs, including nevirapine, delavirdine (discontinued), etravirine, elsulfavirine, efavirenz, rilpivirine, and doravirine. Future development of NNRTIs includes: (i) better resistance and cross-resistance profiles; (ii) reduction of drug burden by optimizing two-drug or three-drug combinations; and (iii) improvement of patient adherence by novel long-acting formulations with weekly or monthly administration. Overall, NNRTIs play an important role in the management of HIV-1 infections, especially in resource-limited countries."

Journal • Review

Hit identification and drug repositioning of potential non-nucleoside reverse transcriptase inhibitors by structure-based approach using computational tools (part II). (PubMed, J Biomol Struct Dyn) - "Etravirine, efavirenz, nevirapine, rilpivirine and delavirdine are the marketed NNRTIs available. All the results obtained from different databases are compiled, interpreted and five molecules were subjected to molecular dynamic studies to further confirm the prediction and identified hit molecules for in vitro screening as potential NNRTIs. Communicated by Ramaswamy H. Sarma."

Journal

Prevalence of predicted resistance to Doravirine in HIV-1 positive patients after exposure to non-nucleoside reverse transcriptase inhibitors. (PubMed, Int J Antimicrob Agents) - "In Italy, DOR resistance is uncommon among patients experienced to NNRTI, confirming a distinguishing resistance pattern within NNRTI. However, previous EFV and ETV experience poses a higher risk of DOR resistance. These results support the use of DOR in patients with NNRTI experience."

Clinical • Journal