Substitution of a hydrogen atom with its heavy isotope deuterium entails the addition of one neutron to a molecule. Despite being a subtle change, this structural modification, known as deuteration, may improve the pharmacokinetic and/or toxicity profile of drugs, potentially translating into improvements in efficacy and safety compared with the non-deuterated counterparts. Initially, efforts to exploit this potential primarily led to the development of deuterated analogues of marketed drugs through a ‘deuterium switch’ approach, such as deutetrabenazine, which became the first deuterated drug to receive FDA approval in 2017. In the past few years, the focus has shifted to applying deuteration in novel drug discovery, and the FDA approved the pioneering de novo deuterated drug deucravacitinib in 2022. In this Review, we highlight key milestones in the field of deuteration in drug discovery and development, emphasizing recent and instructive medicinal chemistry programmes and discussing the opportunities and hurdles for drug developers, as well as the questions that remain to be addressed. Substituting a hydrogen atom with its heavy isotope deuterium may improve the pharmacokinetic and/or toxicity profile of a drug compared with its non-deuterated counterpart. This article highlights milestones in the field of deuteration in drug discovery and development, and discusses recent examples of its application, which have shifted towards deuteration of novel drug candidates instead of developing deuterated analogues of marketed drugs. 

/pdf/deuterium-in-drug-discovery-progress-opportunities-and-2vf7zlsi.pdf

Deuterium in drug discovery: progress, opportunities and challenges

Nirmatrelvir–ritonavir has been authorized for emergency use by many countries for the treatment of coronavirus disease 2019 (Covid-19). However, the supply falls short of the global demand, which creates a need for more options. VV116 is an oral antiviral agent with potent activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). 

https://www.nejm.org/doi/pdf/10.1056/NEJMoa2208822?articleTools=true

VV116 versus Nirmatrelvir–Ritonavir for Oral Treatment of Covid-19

Abstract The outbreak of COVID-19 has become a global crisis, and brought severe disruptions to societies and economies. Until now, effective therapeutics against COVID-19 are in high demand. Along with our improved understanding of the structure, function, and pathogenic process of SARS-CoV-2, many small molecules with potential anti-COVID-19 effects have been developed. So far, several antiviral strategies were explored. Besides directly inhibition of viral proteins such as RdRp and M pro , interference of host enzymes including ACE2 and proteases, and blocking relevant immunoregulatory pathways represented by JAK/STAT, BTK, NF-κB, and NLRP3 pathways, are regarded feasible in drug development. The development of small molecules to treat COVID-19 has been achieved by several strategies, including computer-aided lead compound design and screening, natural product discovery, drug repurposing, and combination therapy. Several small molecules representative by remdesivir and paxlovid have been proved or authorized emergency use in many countries. And many candidates have entered clinical-trial stage. Nevertheless, due to the epidemiological features and variability issues of SARS-CoV-2, it is necessary to continue exploring novel strategies against COVID-19. This review discusses the current findings in the development of small molecules for COVID-19 treatment. Moreover, their detailed mechanism of action, chemical structures, and preclinical and clinical efficacies are discussed. 

/pdf/small-molecules-in-the-treatment-of-covid-19-313d7e1y.pdf

Small molecules in the treatment of COVID-19

The ongoing COVID-19 pandemic has resulted in millions of deaths globally, highlighting the need to develop potent prophylactic and therapeutic strategies against SARS-CoV-2. Small molecule inhibitors (remdesivir, Paxlovid, and molnupiravir) are essential complements to vaccines and play important roles in clinical treatment of SARS-CoV-2. Many advances have been made in development of anti-SARS-CoV-2 inhibitors in China, but progress in discovery and characterization of pharmacological activity, antiviral mechanisms, and clinical efficacy are limited. We review development of small molecule anti-SARS-CoV-2 drugs (azvudine [approved by the NMPA of China on July 25, 2022], VV116 [approved by the NMPA of China on January 29, 2023], FB2001, WPV01, pentarlandir, and cepharanthine) in China and summarize their pharmacological activity, potential mechanisms of action, clinical trials and use, and important milestones in their discovery. The role of structural biology in drug development is also reviewed. Future studies should focus on development of diverse second-generation inhibitors with excellent oral bioavailability, superior plasma half-life, increased antiviral activity against SARS-CoV-2 and its variants, high target specificity, minimal side effects, reduced drug-drug interactions, and improved lung histopathology. 

Bench-to-bedside: Innovation of small molecule anti-SARS-CoV-2 drugs in China

Duration of viable virus shedding and polymerase chain reaction positivity of the SARS-CoV-2 Omicron variant in the upper respiratory tract: a systematic review and meta-analysis

ABSTRACT Omicron variant of SARS-CoV-2 has become the predominant variant worldwide. VV116 is an oral drug with robust anti-SARS-CoV-2 efficacy in preclinical studies. We conducted an open, prospective cohort study to evaluate its safety and effectiveness in Chinese participants infected with the omicron variant from March 8th, 2022 to March 24th, 2022. 136 hospitalized nonsevere patients confirmed with COVID-19 were enrolled including 60 patients who received VV116 (300 mg, BID×5 days) in the treatment group and 76 patients who didn’t receive VV116 in the control group besides standard treatment. Viral load shedding time and adverse events were collected during the follow-up. There was no significant difference in baseline characteristics between the VV116 group and the control group, except for a higher symptom prevalence in the control group (P = 0.021). The median time from the first positive test to the first VV116 administration was 5 (range: 2-10) days. Participants who received VV116 within 5 days since the first positive test had a shorter viral shedding time than the control group (8.56 vs 11.13 days), and cox regression analysis showed adjusted HR of 2.37 [95%CI 1.50-3.75], P < 0.001. In symptomatic subgroup, VV116 group had a shorter viral shedding time than the control group (P = 0.016). A total of 9 adverse events with no serious adverse events were reported in the VV116 group, all of them were resolved without intervention. VV116 is a safe, effective oral antiviral drug, which shows a better performance within the early onset of omicron infection.

https://doi.org/10.1080/22221751.2022.2078230

An open, prospective cohort study of VV116 in Chinese participants infected with SARS-CoV-2 omicron variants

Objective
To observe the influence of nasal administration of dexmedetomidine after induction of anesthesia on agitation of children in ophthalmologic surgery.


Methods
The study was designed as a randomized, double-blind and controlled trial. The children who underwent the ophthalmologic surgery in Department of Ophthalmology, Beijing Tongren Hospital from March to October 2015 were divided into the dexmedetomidine group and the control group by a table of random number. After the induction of anesthesia, all the children received the laryngeal mask (LMA) and the intranasal drugs were sprayed through the nasal mucosal drug delivery device (LMA MAD Nasal™). The dexmedetomidine group received hydrochloride dexmedetomidine injection (1 μg/kg) and the control group received 0.9% sodium chloride injection (0.01 ml/kg). The separation condition between the children and the parents in the 2 groups were judged by Ibrahim's 4 comment method before operation. The children's heart rate, systolic blood pressure, respiratory frequency and pulse oxygen saturation (SpO2) were recorded at the different time points (before induction momentarily, 2 minutes after laryngeal mask insertion, 10 minutes after giving the intranasal drugs, 10 minutes after the starting of operation and the end of operation, respectively). The anesthesia time, operation time, staying time in post anesthesia care unit (PACU) and postoperative emergence agitation were also recorded. The children'waking condition in PACU were evaluated by Sundaram's 4-point score after operation.


Results
A total of 97 children were enrolled in this study. The dexmedetomidine group comprised 47 cases and the control group 50 cases. The differences in age, sex and body weight between the 2 groups were not statistically significant (all P>0.05). The number of cases who had separation difficulty in the dexmedetomidine group and the control group were 26 (55.3%) and 18 (36.0%), respectively. The differences was not statistically significant. The differences in heart rate, systolic pressure; respiratory frequency, SpO2 and staying time in PACU between the children in the 2 groups at different time points during perioperative period were not statistically significant (all P>0.05). The incidence of emergence agitation during recovery period in the dexmedetomidine group was lower than that in the control group[14.9%(7/47) vs 40.0%(20/50)], and the difference was statistically significant (P=0.007).


Conclusion
Nasal administration of dexmedetomidine after induction of anesthesia (1 μg/kg) may decrease the incidence of emergence agitation during recovery period after general anesthesia and be propitious to children'postoperative recovery.


Key words: 
Dexmedetomidine; Intranasal; Administration, intranasal; Child; Agitation

Randomized controlled trial on influence of nasal administration of dexmedetomidine after induction of anesthesia on agitation of children in ophthalmologic surgery

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An open, prospective cohort study of VV116 in Chinese participants infected with SARS-CoV-2 omicron variants

Randomized controlled trial on influence of nasal administration of dexmedetomidine after induction of anesthesia on agitation of children in ophthalmologic surgery