scholarly journals The adenosine analogue prodrug ATV006 is orally bioavailable and has potent preclinical efficacy against SARS-CoV-2 and its variants

2021 ◽  
Author(s):  
Liu Cao ◽  
Yingjun Li ◽  
Sidi Yang ◽  
Guanguan Li ◽  
Qifan Zhou ◽  
...  
Keyword(s):  
Lung Damage ◽  
Oral Drug ◽  
Drug Candidate ◽  
Cynomolgus Monkeys ◽  
Viral Loads ◽  
Antiviral Efficacy ◽  
Limited Efficacy ◽  
Adenosine Analogue ◽  
Preclinical Efficacy ◽  
Orally Bioavailable

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes the COVID-19 pandemic, is rapidly evolving. Due to the limited efficacy of vaccination in prevention of SARS-CoV-2 transmission and continuous emergence of variants of concern (VOC), including the currently most prevalent Delta variant, orally bioavailable and broadly efficacious antiviral drugs are urgently needed. Previously we showed that adenosine analogue 69-0 (also known as GS-441524), possesses potent anti-SARS-CoV-2 activity. Herein, we report that esterification of the 5-hydroxyl moieties of 69-0 markedly improved the antiviral potency. The 5-hydroxyl -isobutyryl prodrug, ATV006, showed excellent oral bioavailability in rats and cynomolgus monkeys and potent antiviral efficacy against different VOCs of SARS-CoV-2 in cell culture and three mouse models. Oral administration of ATV006 significantly reduced viral loads, alleviated lung damage and rescued mice from death in the K18-hACE2 mouse model challenged with the Delta variant. Moreover, ATV006 showed broad antiviral efficacy against different mammal-infecting coronaviruses. These indicate that ATV006 represents a promising oral drug candidate against SARS-CoV-2 VOCs and other coronaviruses.

scholarly journals Antiviral Efficacy upon Administration of a HepDirect Prodrug of 2′-C-Methylcytidine to Hepatitis C Virus-Infected Chimpanzees

2011 ◽  
Vol 55 (8) ◽  
pp. 3854-3860 ◽  
Author(s):  
Steven S. Carroll ◽  
Kenneth Koeplinger ◽  
Marissa Vavrek ◽  
Nanyan Rena Zhang ◽  
Laurence Handt ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Sustained Viral Response ◽  
Pegylated Interferon ◽  
Nucleoside Triphosphate ◽  
Current Standard ◽  
Viral Loads ◽  
Antiviral Efficacy ◽  
Oral And Intravenous Dosing

ABSTRACTHepatitis C virus (HCV) infects an estimated 170 million individuals worldwide, and the current standard of care, a combination of pegylated interferon alpha and ribavirin, is efficacious in achieving sustained viral response in ∼50% of treated patients. Novel therapies under investigation include the use of nucleoside analog inhibitors of the viral RNA-dependent RNA polymerase. NM283, a 3′-valyl ester prodrug of 2′-C-methylcytidine, has demonstrated antiviral efficacy in HCV-infected patients (N. Afdhal et al., J. Hepatol.46[Suppl. 1]:S5, 2007; N. Afdhal et al., J. Hepatol.44[Suppl. 2]:S19, 2006). One approach to increase the antiviral efficacy of 2′-C-methylcytidine is to increase the concentration of the active inhibitory species, the 5′-triphosphate, in infected hepatocytes. HepDirect prodrug technology can increase intracellular concentrations of a nucleoside triphosphate in hepatocytes by introducing the nucleoside monophosphate into the cell, bypassing the initial kinase step that is often rate limiting. Screening for 2′-C-methylcytidine triphosphate levels in rat liver after oral dosing identified 1-[3,5-difluorophenyl]-1,3-propandiol as an efficient prodrug modification. To determine antiviral efficacyin vivo, the prodrug was administered separately via oral and intravenous dosing to two HCV-infected chimpanzees. Circulating viral loads declined by ∼1.4 log10IU/ml and by >3.6 log10IU/ml after oral and intravenous dosing, respectively. The viral loads rebounded after the end of dosing to predose levels. The results indicate that a robust antiviral response can be achieved upon administration of the prodrug.

scholarly journals Mathematical modeling explains differential SARS CoV-2 kinetics in lung and nasal passages in remdesivir treated rhesus macaques

2020 ◽  
Author(s):  
Ashish Goyal ◽  
Elizabeth R. Duke ◽  
E. Fabian Cardozo-Ojeda ◽  
Joshua T. Schiffer
Keyword(s):  
Viral Load ◽  
Rhesus Macaques ◽  
Natural Infection ◽  
Antiviral Effect ◽  
Human Infection ◽  
Lung Damage ◽  
Viral Loads ◽  
Subsequent Decrease ◽  
Drug Potency ◽  
Nasal Passages

AbstractRemdesivir was recently demonstrated to decrease recovery time in hospitalized patients with SARS-CoV-2 infection. In rhesus macaques, early initiation of remdesivir therapy prevented pneumonia and lowered viral loads in the lung, but viral loads increased in the nasal passages five days after therapy. We developed mathematical models to explain these results. We identified that 1) drug potency is slightly higher in nasal passages than in lungs, 2) viral load decrease in lungs relative to nasal passages during therapy because of infection-dependent generation of refractory cells in the lung, 3) incomplete drug potency in the lung that decreases viral loads even slightly may allow substantially less lung damage, and 4) increases in nasal viral load may occur due to a slight blunting of peak viral load and subsequent decrease of the intensity of the innate immune response, as well as a lack of refractory cells. We also hypothesize that direct inoculation of the trachea in rhesus macaques may not recapitulate natural infection as lung damage occurs more abruptly in this model than in human infection. We demonstrate with sensitivity analysis that a drug with higher potency could completely suppress viral replication and lower viral loads abruptly in the nasal passages as well as the lung.One Sentence SummaryWe developed a mathematical model to explain why remdesivir has a greater antiviral effect on SARS CoV-2 in lung versus nasal passages in rhesus macaques.

scholarly journals In vitro and in vivo pharmacokinetic characterization of LMT-28 as a novel small molecular interleukin-6 inhibitor

2020 ◽  
Vol 33 (4) ◽  
pp. 670-677
Author(s):  
Sung-Hoon Ahn ◽  
Tae-Hwe Heo ◽  
Hyun-Sik Jun ◽  
Yongseok Choi
Keyword(s):  
Mdck Cell ◽  
Interleukin 6 ◽  
Cell Permeability ◽  
Oral Drug ◽  
Drug Candidate ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies ◽  
Pharmacokinetic Properties

Objective: Interleukin-6 (IL-6) is a T cell-derived B cell stimulating factor which plays an important role in inflammatory diseases. In this study, the pharmacokinetic properties of LMT-28 including physicochemical property, <i>in vitro</i> liver microsomal stability and an <i>in vivo</i> pharmacokinetic study using BALB/c mice were characterized.Methods: LMT-28 has been synthesized and is being developed as a novel therapeutic IL-6 inhibitor. The physicochemical properties and <i>in vitro</i> pharmacokinetic profiles such as liver microsomal stability and Madin-Darby canine kidney (MDCK) cell permeability assay were examined. For <i>in vivo</i> pharmacokinetic studies, pharmacokinetic parameters using BALB/c mice were calculated.Results: The logarithm of the partition coefficient value (LogP; 3.65) and the apparent permeability coefficient values (P<sub>app</sub>; 9.7×10<sup>–6</sup> cm/s) showed that LMT-28 possesses a moderate-high cell permeability property across MDCK cell monolayers. The plasma protein binding rate of LMT-28 was 92.4% and mostly bound to serum albumin. The metabolic half-life (t<sub>1/2</sub>) values of LMT-28 were 15.3 min for rat and 21.9 min for human at the concentration 1 μM. The area under the plasma drug concentration-time curve and C<sub>max</sub> after oral administration (5 mg/kg) of LMT-28 were 302±209 h∙ng/mL and 137±100 ng/mL, respectively.Conclusion: These data suggest that LMT-28 may have good physicochemical and pharmacokinetic properties and may be a novel oral drug candidate as the first synthetic IL-6 inhibitor to ameliorate mammalian inflammation.

scholarly journals Progress Towards a Large-Scale Synthesis of Molnupiravir (MK-4482, EIDD-2801) from Cytidine

2021 ◽  
Author(s):  
Grace P. Ahlqvist ◽  
Catherine P. McGeough ◽  
Chris Senanayake ◽  
Joseph D. Armstrong ◽  
Ajay Yadaw ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Large Scale ◽  
Drug Product ◽  
Second Step ◽  
Drug Candidate ◽  
Patent Literature ◽  
Enzymatic Acylation ◽  
Orally Bioavailable ◽  
The Cost ◽  
Initial Route

<div> <div> <div> <p>Molnupiravir (MK-4482, EIDD-2801) is a promising orally bioavailable drug candidate for treatment of COVID-19. Herein we describe a supply-centered and chromatography-free synthesis of molnupiravir from cytidine, consisting of two steps: a selective enzymatic acylation followed by transamination to yield the final drug product. Both steps have been successfully performed on decagram scale: the first step at 200 g, and the second step at 80 g. Overall, molnupiravir has been obtained in a 41% overall isolated yield compared to a maximum 17% isolated yield in the patented route. This route provides many advantages to the initial route described in the patent literature and would decrease the cost of this pharmaceutical should it prove safe and efficacious in ongoing clinical trials.</p> </div> </div> </div>

Abstract P221: First-In-Class Anti-Spastic Drug Candidate (MPH-220) Efficiently Relaxes Spastic Muscles and Improves Motor Functions in Gait Disorder in Preclinical Studies

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Mate Gyimesi ◽  
Adam Horvath ◽  
Demeter Turos ◽  
Mate Penzes ◽  
Csilla Kurdi ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Nervous System ◽  
Side Effects ◽  
Hormone Receptors ◽  
Muscle Tone ◽  
Muscle Stiffness ◽  
Oral Drug ◽  
Drug Candidate ◽  
Phase I Clinical Trials ◽  
Cardiovascular Side Effects

Post-stroke muscle spasticity affects 37% of stroke survivors and disables self-supporting life management. There is a high unmet medical need for an efficient antispastic drug because current muscle relaxants are often of limited efficacy and cause severe neurological and cardiovascular side effects due to targeting the central or peripheral nervous system. We developed a new-generation anti-spastic oral drug, MPH-220, which efficiently relaxes spastic skeletal muscles and lacks cardiovascular and neurological adverse effects because it selectively targets skeletal myosin, the contractile protein of muscles. MPH-220 is an efficient skeletal muscle specific actomyosin relaxant demonstrated on human muscle samples. Orally administered MPH-220 reduces muscle force of living rats without cardiovascular side effects. Brain-damage induced spastic animals showed drastic improvement in gait disorders upon oral MPH-220 treatment resulting in significantly straightened body posture, reduced number of spontaneous falling and cramping, and more ordered limb positions. Due to selective accumulation of MPH-220 in skeletal muscle tissues, antispastic effect was maintained for more than 10 hours. Due to its mechanism of action MPH-220 does not cause complete loss of muscle tone even at high doses. Furthermore, MPH-220 has excellent ADMET properties for oral administration: it is highly absorptive, non-mutagenic and has no effects on hERG channels, kinases, nuclear hormone receptors and GPCRs. Considering these results, MPH-220 is a promising anti-spastic oral drug candidate, which provides potential nervous system-independent therapies for spasticity and muscle stiffness without cardiovascular and neuronal side effects. Phase I clinical trials are scheduled for the beginning of 2021. Funded by the Hungarian National Research, Development and Innovation Office (NVKP 16-1-2016-0051 and PIACI-KFI-2019-00488).

scholarly journals Pharmacokinetics of SCH 56592, a New Azole Broad-Spectrum Antifungal Agent, in Mice, Rats, Rabbits, Dogs, and Cynomolgus Monkeys

2000 ◽  
Vol 44 (3) ◽  
pp. 727-731 ◽  
Author(s):  
Amin A. Nomeir ◽  
Pramila Kumari ◽  
Mary Jane Hilbert ◽  
Samir Gupta ◽  
David Loebenberg ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Oral Bioavailability ◽  
Antifungal Agent ◽  
Fungal Infections ◽  
Effective Dosage ◽  
Terminal Phase ◽  
Drug Candidate ◽  
Multiple Dosing ◽  
Cynomolgus Monkeys ◽  
Drug Concentrations

ABSTRACT SCH 56592 is a new broad-spectrum azole antifungal agent that is in phase 3 clinical trials for the treatment of serious systemic fungal infections. The pharmacokinetics of this drug candidate were evaluated following its intravenous (i.v.) or oral (p.o.) administration as a solution in hydroxypropyl-β-cyclodextrin (HPβCD) or oral administration as a suspension in 0.4% methylcellulose (MC) in studies involving mice, rats, rabbits, dogs, and cynomolgus monkeys. SCH 56592 was orally bioavailable in all species. The oral bioavailability was higher with the HPβCD solution (range, 52 to ∼100%) than from the MC suspension (range, 14 to 48%) and was higher in mice (∼100% [HPβCD] and 47% [MC]), rats (∼66% [HPβCD] and 48% [MC]), and dogs (72% [HPβCD] and 37% [MC]) than in monkeys (52% [HPβCD] and 14% [MC]). In rabbits, high concentrations in serum suggested good oral bioavailability with the MC suspension. The i.v. terminal-phase half-lives were 7 h in mice and rats, 15 h in dogs, and 23 h in monkeys. In rabbits, the oral half-life was 9 h. In species given increasing oral doses (mice, rats, and dogs), serum drug concentrations were dose related. Food produced a fourfold increase in serum drug concentrations in dogs. Multiple daily doses of 40 mg of SCH 56592/kg of body weight for eight consecutive days to fed dogs resulted in higher concentrations in serum, indicating accumulation upon multiple dosing, with an accumulation index of approximately 2.6. Concentrations above the MICs and minimum fungicidal concentrations for most organisms were observed at 24 h following a single oral dose in MC suspension in all five species studied (20 mg/kg for mice, rats, and rabbits and 10 mg/kg for dogs and monkeys), suggesting that once-daily administration of SCH 56592 in human subjects would be a therapeutically effective dosage regimen.

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