ABSTRACT
AIMS: To predict potential drugs for COVID-19 by using molecular docking for virtual screening of drugs approved for other clinical applications. BACKGROUND: SARS-CoV-2 is the betacoronavirus responsible for the COVID-19 pandemic. It was listed as a potential global health threat by the WHO due to high mortality, high basic reproduction number, and lack of clinically approved drugs and vaccines. The genome of the virus responsible for COVID-19 has been sequenced. In addition, the three-dimensional structure of the main protease has been determined experimentally. OBJECTIVE: To identify potential drugs that can be repurposed for treatment of COVID-19 by using molecular docking based virtual screening of all approved drugs. METHODS: A list of drugs approved for clinical use was obtained from the SuperDRUG2 database. The structure of the target in the apo form, as well as structures of several target-ligand complexes, were obtained from RCSB PDB. The structure of SARS-CoV-2 Mpro determined from X-ray diffraction data was used as the target. Data regarding drugs in clinical trials for COVID-19 was obtained from clinicaltrials.org. Input for molecular docking based virtual screening was prepared by using Obabel and customized python, bash, and awk scripts. Molecular docking calculations were carried out with Vina and SMINA, and the docked conformations were analyzed and visualized with PLIP, Pymol, and Rasmol. RESULTS: Among the drugs that are being tested in clinical trials for COVID-19, Danoprevir and Darunavir were predicted to have the highest binding affinity for the Main protease (Mpro) target of SARS-CoV-2. Saquinavir and Beclabuvir were identified as the best novel candidates for COVID-19 therapy by using Virtual Screening of drugs approved for other clinical indications. CONCLUSION: Protease inhibitors approved for treatment of other viral diseases have the potential to be repurposed for treatment of COVID-19.
Subject(s)
Antiviral Agents/pharmacology , COVID-19 Drug Treatment , COVID-19/virology , Drug Evaluation, Preclinical , Molecular Docking Simulation , SARS-CoV-2/drug effects , Antiviral Agents/chemistry , Benzazepines/chemistry , Benzazepines/pharmacology , Cyclopropanes/chemistry , Cyclopropanes/pharmacology , Darunavir/chemistry , Darunavir/pharmacology , Drug Repositioning , High-Throughput Screening Assays , Humans , Indoles/chemistry , Indoles/pharmacology , Isoindoles/chemistry , Isoindoles/pharmacology , Lactams, Macrocyclic/chemistry , Lactams, Macrocyclic/pharmacology , Proline/analogs & derivatives , Proline/chemistry , Proline/pharmacology , Saquinavir/chemistry , Saquinavir/pharmacology , Sulfonamides/chemistry , Sulfonamides/pharmacologySubject(s)
Benzazepines/pharmacology , Hepatitis C, Chronic/drug therapy , Imidazoles/pharmacology , Indoles/pharmacology , Isoquinolines/pharmacology , Sulfonamides/pharmacology , Benzazepines/chemistry , Benzazepines/therapeutic use , Carbamates , Clinical Trials as Topic , Drug Combinations , Drug Evaluation, Preclinical , Drug Resistance, Viral , Humans , Imidazoles/chemistry , Imidazoles/therapeutic use , Indoles/chemistry , Indoles/therapeutic use , Isoquinolines/chemistry , Isoquinolines/therapeutic use , Pyrrolidines , Sulfonamides/chemistry , Sulfonamides/therapeutic use , Tablets , Valine/analogs & derivativesABSTRACT
BACKGROUND: Lateral hypothalamus (LH) involves in modulation of tonic pain. Regarding the direct and indirect neural connections between the LH and nucleus accumbens (NAc), we aimed to examine the pain modulatory role of NAc dopamine receptors in modulation of LH-induced analgesia in the formalin test. METHODS: Vehicle-control groups received saline or DMSO into the NAc and saline into the LH. Carbachol-control groups received carbachol (250 nmol/L) into the LH, 5 min after saline or DMSO injection into the NAc. In treatment groups, intra-NAc administration of SCH-23390 or sulpiride (D1-and D2-like dopamine receptor antagonists, respectively) was performed 5 min before carbachol injection. Formalin test was done in all rats 5 min after the second injection. RESULTS: The blockade of NAc dopamine receptors reduced carbachol-induced antinociception during both phases of formalin test and reduction in LH-induced analgesia during the late phase was more than that during the early phase. Furthermore, contribution of D2-like dopamine receptors to mediation of anti-hyperalgesic effect of carbachol was greater than that of D1-like dopamine receptors during the late phase. CONCLUSIONS: The findings suggest that LH-VTA-NAc circuit is contributed to the modulation of formalin-induced pain. These findings demonstrate that transmission at D1- and D2-like dopamine receptors mediates the LH-induced analgesia. SIGNIFICANCE: Blockade of accumbal dopamine receptors attenuated analgesia induced by carbachol injection into the lateral hypothalamus during both phases of formalin test. Effect of blockade of D1- and D2-like dopamine receptors on reduction in antinociception was more during the late phase. Contribution of D2-like dopamine receptors to mediation of antinociception during the late phase was greater than the early phase.
Subject(s)
Benzazepines/pharmacology , Carbachol/pharmacology , Hypothalamus/physiology , Nucleus Accumbens/chemistry , Pain Measurement/drug effects , Pain/prevention & control , Receptors, Dopamine/chemistry , Sulpiride/pharmacology , Analgesia , Animals , Benzazepines/chemistry , Male , Nucleus Accumbens/physiology , Rats , Rats, Wistar , Receptors, Dopamine/physiologyABSTRACT
Herein, we describe the synthesis, antiviral structure-activity relationships (SAR), metabolic stability, and pharmacokinetic (PK) properties for a series of cyclopropylindolobenzazepine acylsulfonamide HCV NS5B polymerase inhibitors. Optimization of SAR, metabolic stability and PK led to the identification of compound 19 which was advanced into pre-IND enabling toxicology studies.
Subject(s)
Antiviral Agents/chemistry , Hepacivirus/enzymology , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Sulfonamides/chemistry , Administration, Oral , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacokinetics , Benzazepines/chemistry , Drug Evaluation, Preclinical , Half-Life , Humans , Macaca fascicularis , Microsomes, Liver/metabolism , RNA-Dependent RNA Polymerase/metabolism , Rats , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/pharmacokineticsABSTRACT
The weight-loss drug lorcaserin, a FDA approved anorectic drug, was isolated from the dietary supplement "Lose quickly" claimed to be a pure natural fast slimming diet pill. After its purification by means of preparative liquid chromatography, its structure was characterized using LC-UV, NMR, MS, MS/MS, and IR spectroscopy. The amount of lorcaserin measured by qNMR was 6.6mg/capsule.
Subject(s)
Benzazepines/chemistry , Dietary Supplements/analysis , Chromatography, Liquid/methods , Herbal Medicine/methods , Magnetic Resonance Spectroscopy/methods , Tandem Mass Spectrometry/methodsABSTRACT
This Letter describes the discovery of a novel series of H3 receptor antagonists. The initial medicinal chemistry strategy focused on deconstructing and simplifying an early screening hit which rapidly led to the discovery of a novel series of H3 receptor antagonists based on the benzazepine core. Employing an H3 driven pharmacodynamic model, the series was then further optimised through to a lead compound that showed robust in vivo functional activity and possessed overall excellent developability properties.
Subject(s)
Benzazepines/chemistry , Histamine H3 Antagonists/chemistry , Receptors, Histamine H3/chemistry , Animals , Benzazepines/chemical synthesis , Benzazepines/pharmacokinetics , Cytochrome P-450 CYP2D6/chemistry , Cytochrome P-450 CYP2D6/metabolism , Drug Evaluation, Preclinical , Half-Life , Histamine H3 Antagonists/chemical synthesis , Histamine H3 Antagonists/pharmacokinetics , Humans , Microsomes, Liver/metabolism , Protein Binding , Rats , Receptors, Histamine H3/genetics , Receptors, Histamine H3/metabolism , Recombinant Proteins/biosynthesis , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Structure-Activity RelationshipABSTRACT
Antileishmanial paullone-chalcone hybrid molecules display antiparasitic activity against Trypanosoma brucei rhodesiense blood stream forms, albeit with low selectivity against human THP-1 cells. In order to develop less toxic analogues, paullones with acrylamide or aryl substituents in 2-position were synthesized, of which the latter exhibited potent antiparasitic activity with excellent selectivity profiles. The most potent compound identified in this study was 9-tert-butyl-2-(4-morpholinophenyl)paullone (3i) which inhibited the parasites at submicromolar concentrations (GI50 = 510 nM) with a selectivity index of 157.
Subject(s)
Benzazepines/pharmacology , Trypanocidal Agents/pharmacology , Trypanosoma brucei rhodesiense/drug effects , Benzazepines/chemical synthesis , Benzazepines/chemistry , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Molecular Structure , Parasitic Sensitivity Tests , Structure-Activity Relationship , Trypanocidal Agents/chemical synthesis , Trypanocidal Agents/chemistryABSTRACT
Cleavage and reconstitution of a bond in the piperidine ring of ifenprodil (1) leads to 7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-1-ols, a novel class of NR2B-selective NMDA receptor antagonists. The secondary amine 7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-1-ol (12), which was synthesized in six steps starting from 2-phenylethylamine 3, represents the central building block for the introduction of several N-linked residues. A distance of four methylene units between the basic nitrogen atom and the phenyl residue in the side chain results in high NR2B affinity. The 4-phenylbutyl derivative 13 (WMS-1405, K(i)=5.4 nM) and the conformationally restricted 4-phenylcyclohexyl derivative 31 (K(i)=10 nM) represent the most potent NR2B ligands of this series. Whereas 13 shows excellent selectivity, the 4-phenylcyclohexyl derivative 31 also interacts with sigma(1) (K(i)=33 nM) and sigma(2) receptors (K(i)=82 nM). In the excitotoxicity assay the phenylbutyl derivative 13 inhibits the glutamate-induced cytotoxicity with an IC(50) value of 360 nM, indicating that 13 is an NMDA antagonist.
Subject(s)
Benzazepines/chemistry , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Animals , Benzazepines/chemical synthesis , Benzazepines/toxicity , Binding Sites , Cell Line , Drug Design , Drug Evaluation, Preclinical , Mice , Piperidines/chemistry , Receptors, N-Methyl-D-Aspartate/metabolism , Structure-Activity RelationshipABSTRACT
We have continued to explore spirobenzazepines as vasopressin receptor antagonists to follow up on RWJ-339489 (2), which had advanced into preclinical development. Further structural modifications were pursued to find a suitable backup compound for human clinical studies. Thus, we identified carboxylic acid derivative 3 (RWJ-676070; JNJ-17158063) as a potent, balanced vasopressin V(1a)/V(2) receptor antagonist with favorable properties for clinical development. Compound 3 is currently undergoing human clinical investigation.
Subject(s)
Antidiuretic Hormone Receptor Antagonists , Benzazepines/chemistry , Spiro Compounds/chemistry , Animals , Antihypertensive Agents/administration & dosage , Antihypertensive Agents/chemistry , Antihypertensive Agents/metabolism , Antihypertensive Agents/pharmacokinetics , Benzazepines/administration & dosage , Benzazepines/pharmacokinetics , Benzazepines/pharmacology , Drug Evaluation, Preclinical , Female , Humans , Male , Rats , Rats, Long-Evans , Receptors, Vasopressin/metabolism , Receptors, Vasopressin/physiology , Spiro Compounds/administration & dosage , Spiro Compounds/metabolism , Spiro Compounds/pharmacokinetics , Spiro Compounds/pharmacology , Vasopressins/metabolismABSTRACT
The metabolism and disposition of varenicline (7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine), a partial agonist of the nicotinic acetylcholine receptor for the treatment of tobacco addiction, was examined in rats, mice, monkeys, and humans after oral administration of [14C]varenicline. In the circulation of all species, the majority of drug-related material was composed of unchanged varenicline. In all four species, drug-related material was primarily excreted in the urine. A large percentage was excreted as unchanged parent drug (90, 84, 75, and 81% of the dose in mouse, rat, monkey, and human, respectively). Metabolites observed in excreta arose via N-carbamoyl glucuronidation and oxidation. These metabolites were also observed in the circulation, in addition to metabolites that arose via N-formylation and formation of a novel hexose conjugate. Experiments were conducted using in vitro systems to gain an understanding of the enzymes involved in the formation of the N-carbamoylglucuronide metabolite in humans. N-Carbamoyl glucuronidation was catalyzed by UGT2B7 in human liver microsomes when incubations were conducted under a CO2 atmosphere. The straightforward dispositional profile of varenicline should simplify its use in the clinic as an aid in smoking cessation.
Subject(s)
Benzazepines/metabolism , Benzazepines/pharmacokinetics , Quinoxalines/metabolism , Quinoxalines/pharmacokinetics , Administration, Oral , Animals , Area Under Curve , Benzazepines/chemistry , Benzazepines/urine , Carbon Radioisotopes , Chromatography, High Pressure Liquid/methods , Drug Evaluation, Preclinical/methods , Feces/chemistry , Female , Glucuronides/chemistry , Glucuronides/metabolism , Half-Life , Haplorhini , Humans , Male , Mass Spectrometry/methods , Mice , Monosaccharides/chemistry , Monosaccharides/metabolism , Nicotinic Agonists/chemistry , Nicotinic Agonists/metabolism , Nicotinic Agonists/pharmacokinetics , Pentoses/metabolism , Quinoxalines/chemistry , Quinoxalines/urine , Rats , Rats, Sprague-Dawley , Receptors, Nicotinic/metabolism , Species Specificity , VareniclineABSTRACT
To find potent and selective antagonists of the arginine vasopressin (AVP) V1A receptor, optimization studies of compounds structurally related to (Z)-N-{4'-[(4,4-difluoro-5-carbamoylmethylidene-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl]phenyl}carboxamide were performed. The synthesis and pharmacological properties of these compounds are described. We first investigated the effect of the carboxamide moiety, and found that a 2-methylfuran-3-carbonyl group at this position increased V1A binding affinity and selectivity for the V1A receptor versus the V2 receptor. The amino group of the 5-carbamoylmethylidene moiety was also examined, and a 4-piperidinopiperidino group was found to be optimal at this position. The hemifumarate of compound 12l (YM218) was shown to exhibit potent binding affinity, V1A receptor selectivity, and in vivo antagonist activity.
Subject(s)
Antidiuretic Hormone Receptor Antagonists , Benzazepines/chemistry , Benzazepines/pharmacology , Fluorine/chemistry , Animals , Benzazepines/chemical synthesis , Cells, Cultured , Drug Evaluation, Preclinical , Fluorine/pharmacology , Humans , Male , Molecular Structure , Peptides/chemistry , Peptides/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
The first solid-phase synthesis of zatebradine 1 and its analogues is reported. This has resulted in the preparation of compounds with increased ability to reduce the spontaneous beating of isolated guinea-pig atria in a concentration-dependent manner. One example, 8g, showed a maximum reduction of beating of 80% at 3 microM compared to a reduction of 40% at 3 microM with zatebradine 1.
Subject(s)
Benzazepines/chemistry , Benzazepines/pharmacology , Cardiotonic Agents/chemistry , Cardiotonic Agents/pharmacology , Animals , Atrial Function , Benzazepines/chemical synthesis , Combinatorial Chemistry Techniques , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Guinea Pigs , Heart Atria/drug effects , In Vitro Techniques , Structure-Activity RelationshipABSTRACT
Synthesis of 5,10-dihydro-10-methylindolo[3, 2-b][1]benzazepin-12(11H)-one (2), an isomer of the reported structure for cryptoheptine (1), is presented. Attempts to convert 2 to 1 led to 10-methylindolo[3,2-b][1]benzazepin-12-one (10), an oxidation product of 2 and presumably 1. These results highlight the potential instability of cryptoheptine and cast doubt on its proposed structure.