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We reported the synthesis and anti-RSV or anti-IFV activities of NHC derivatives and 4′-fluorouridine prodrugs, which were evaluated for their chemical stability and PK properties. Tri-isobutyrate ester 1a has potential to be as an antiviral agent.

Aims Glimepiride has good cardiovascular safety. However, whether glimepiride benefits clinical cardiovascular outcomes is unclear. Methods and results A total of 21 451 inpatients with type 2 diabetes (T2D) and chronic heart failure (CHF) were analysed, including 638 who received glimepiride treatment and 20 813 who did not. Propensity score matching yielded 509 pairs (glimepiride and non-glimepiride groups), and both groups were followed up. Kaplan–Meier and Cox regression analyses were used to compare all-cause mortality, cardiovascular mortality, hospitalizations and emergency visits for heart failure, and hospitalizations for acute myocardial infarction or stroke. During follow-up, the all-cause mortality [adjusted hazard ratio (HR), 0.47; 95% confidence interval (CI), 0.35–0.63; P < 0.001], cardiovascular mortality (adjusted HR, 0.34; 95% CI, 0.24–0.48; P < 0.001), and number of hospitalizations and emergency visits for heart failure (adjusted HR, 0.42; 95% CI, 0.36–0.50; P < 0.001) and hospitalizations for acute myocardial infarction or stroke (adjusted HR, 0.53; 95% CI, 0.38–0.73; P < 0.001) were significantly lower in the glimepiride group; the conclusion remained similar in all subgroups. Furthermore, high-dose glimepiride use (2–4 mg/day) was associated with lower cardiovascular mortality than low-dose (1 mg/day) (adjusted HR, 0.55; 95% CI, 0.31–0.99; P = 0.047). Glimepiride exhibited good molecular docking with soluble epoxide hydrolase (sEH) and increased the level epoxyeicosatrienoic acid (EET). Conclusion Long-term continuous glimepiride use is associated with better survival, fewer hospitalizations and emergency visits for heart failure, and fewer hospitalizations for acute myocardial infarction or stroke in patients with T2D and CHF. High-dose glimepiride has greater cardiovascular protective advantages than low-dose glimepiride. The cardiovascular protective effect of glimepiride may be related to the EET level increase through sEH inhibition. Trial registration ClinicalTrials.gov NCT05538819. https://www.clinicaltrials.gov/ct2/show/NCT05538819

A new route for the synthesis of tetrahydrocortisone 3-glucuronide has been developed with cortisone acetate as a starting material. The key step was using lithium tri-tert-butoxyaluminum hydride to reduce the C-3 carbonyl group of 5��-dihydrocortisone acetate (8) to provide 3��-5��-tetrahydrocortisone acetate (5). Then, Koenig���Knorr method was used for glycosylation with glycosyl bromide as the donor, cadmium carbonate as promoter and 4�� molecular sieves as dehydrating agent to give high yield of the desired product. The new route is shorter and gives higher yield than that reported in the literature.

A series of 2'-deoxy carbocyclic nucleosides characterized by various 6'-substitutions were synthesized and evaluated for their antiviral activities against three viruses, including hepatitis B virus (HBV), hepatitis C virus, and influenza virus. The in vitro antiviral assays indicated that these nucleosides only showed inhibitory activities against HBV, and the substituted groups at the 6' position significantly affected the activity. Among them, the guanosine analog 2b bearing a 6'-α-hydroxyl methyl group was the most potent compound with an EC

The development of an industrially scalable synthetic route for 5,7-dichlorotetrahydroisoquinoline-6-carboxylic acid (1), a key starting material for lifitegrast, is described. This route includes ...

A three-step sequence for preparing remdesivir, an important anti-SARS-CoV-2 drug, is described. Employing

Human inflammatory disease, multiple sclerosis (MS), is a demyelinating disease of central nervous system (CNS). The experimental autoimmune encephalomyelitis (EAE) is the most commonly used as experimental model because of its key pathological features' approximation of MS. The interaction between complex elements in immune system and in the CNS determines the MS pathogenesis. However, there is no cure for MS and the treatment for MS still encounters great challenges. Thus, finding a more effective disease-modifying treatment is imminent. In the present study, we investigated whether 9,10-Anhydrodehydroartemisin (ADART), a compound derived from artemisinin, could decrease demyelination in EAE and the underlying mechanisms. In established EAE mice, 100 mg/kg 9,10-Anhydrodehydroartemisinin (ADART) effectively reduced CNS and peripheral immune system infiltration inflammatory cells including CD4+ IFN-γ+ Th1 cells and CD4+ IL-17A+ Th17 cells. Correspondingly, the serum level of IFN-γ and IL-17A was also reduced. In vitro, ADART almost completely inhibited Th17 differentiation, and partially inhibited Th1 differentiation in 10 μM. This research revealed that ADART could be a great promising avenue among current therapies for MS.

Currently, remdesivir is the first and only FDA-approved antiviral drug for COVID-19 treatment. Adequate supplies of remdesivir are highly warranted to cope with this global public health crisis. Herein, we report a Weinreb amide approach for preparing the key intermediate of remdesivir in the glycosylation step where overaddition side reactions are eliminated. Starting from 2,3,5-tri-O-benzyl-d-ribonolactone, the preferred route consisting of three sequential steps (Weinreb amidation, O-TMS protection, and Grignard addition) enables a high-yield (65%) synthesis of this intermediate at a kilogram scale. In particular, the undesirable PhMgCl used in previous methods was successfully replaced by MeMgBr. This approach proved to be suitable for the scalable production of the key remdesivir intermediate.

Porcine epidemic diarrhea (PED) caused by porcine epidemic diarrhea virus (PEDV) is widespread in the world. In recent years, the increased virulence of the virus due to viral variations, has caused great economic losses to the pig industry in many countries. It is always worthy to find effective therapeutic methods for PED. As an important class of antivirals, nucleoside drugs which target viral polymerases have been applied in treating human viral infections for half a century. Herein, we evaluated the anti-PEDV potential of three broad-spectrum antiviral nucleoside analogs, remdesivir (RDV), its parent nucleoside (RDV-N) and β-d-N4-hydroxycytidine (NHC). Among them, RDV-N was the most active agent in Vero E6 cells with EC50 of 0.31 μmol/L, and more potent than RDV (EC50 = 0.74 μmol/L) and NHC (EC50 = 1.17 μmol/L). The activity of RDV-N was further confirmed using an indirect immuno-fluorescence assay. Moreover, RDV-N exhibited a good safety profile in cells and in mice. The high sequence similarity of the polymerase functional domains of PEDV with other five porcine coronaviruses indicated a broader antiviral spectrum for the three compounds. Generally, RDV-N is a promising broad-spectrum antiviral nucleoside, and it would be worthy to make some structural modifications to increase its oral bioavailability.

Herein we disclosed a straightforward synthesis of oxazoline-fused saccharides (oxazolinoses) from peracetylated saccharides and benzonitriles under acidic conditions with stoichiometric amounts of water. The density functional theory (DFT) calculations have revealed the origin of the stereoselectivity and the key role of water in promoting the departure of the acetyl group at C-2. The resulting oxazolinoses can be concisely converted into the corresponding 1,2-cis glycosylamines bearing various protected groups, allowing the access to schisandrin derivatives.

The COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is continuing to spread around the world. GS-441524 is the parent nucleoside of remdesivir which is the first drug approved for the treatment of COVID-19, and demonstrates strong activity against SARS-Cov-2 in vitro and in vivo. Herein, we reported the synthesis of a series of deuterated GS-441524 analogs, which had deuterium atoms up to five at the ribose and the nucleobase moieties. Compared to GS-441524, all the deuterated compounds showed similar inhibitory activities against SARS-CoV-2 in vitro.

A wrench in the works of COVID-19 Understanding the inner workings of the virus that causes coronavirus disease 2019 (COVID-19) may help us to disrupt it. Yin et al. focused on the viral polymerase essential for replicating viral RNA. They determined a structure of the polymerase bound to RNA and to the drug remdesivir. Remdesivir mimics an RNA nucleotide building block and is covalently linked to the replicating RNA, which blocks further synthesis of RNA. The structure provides a template for designing improved therapeutics against the viral polymerase. Science , this issue p. 1499

TPN729 is a novel phosphodiesterase 5 (PDE5) inhibitor used to treat erectile dysfunction in men. Our previous study shows that the plasma exposure of metabolite M3 (N-dealkylation of TPN729) in humans is much higher than that of TPN729. In this study, we compared its metabolism and pharmacokinetics in different species and explored the contribution of its main metabolite M3 to pharmacological effect. We conducted a combinatory approach of ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry-based metabolite identification, and examined pharmacokinetic profiles in monkeys, dogs, and rats following TPN729 administration. A remarkable species difference was observed in the relative abundance of major metabolite M3: i.e., the plasma exposure of M3 was 7.6-fold higher than that of TPN729 in humans, and 3.5-, 1.2-, 1.1-fold in monkeys, dogs, and rats, respectively. We incubated liver S9 and liver microsomes with TPN729 and CYP3A inhibitors, and demonstrated that CYP3A was responsible for TPN729 metabolism and M3 formation in humans. The inhibitory activity of M3 on PDE5 was 0.78-fold that of TPN729 (The IC(50) values of TPN729 and M3 for PDE5A were 6.17 ± 0.48 and 7.94 ± 0.07 nM, respectively.). The plasma protein binding rates of TPN729 and M3 in humans were 92.7% and 98.7%, respectively. It was astonishing that the catalyzing capability of CYP3A4 in M3 formation exhibited seven-fold disparity between different species. M3 was an active metabolite, and its pharmacological contribution was equal to that of TPN729 in humans. These findings provide new insights into the limitation and selection of animal model for predicting the clinical pharmacokinetics of drug candidates metabolized by CYP3A4.

The sirtuins are members of the histone deacetylase family of proteins that participate in a variety of cellular functions and play a close role in cancers. Exploring the proper inhibitors for SIRT...

A safe and efficient synthesis of 6-chloro-5-methylpyridin-2-amine, a key intermediate for lumacaftor, is described, which avoids the utilization of peroxide. In this four-step sequence, starting f...

A concise synthetic route was designed for making telmisartan. The key bis-benzimidazole structure was constructed via the copper-catalyzed cyclization of o-haloarylamidines. By adopting this approach, telmisartan was obtained in a 7-step overall yield of 54% starting from commercially available 3-methyl-4-nitrobenzoic acid, and the use of HNO3/H2SO4 for nitration and polyphosphoric acid (PPA) for cyclization in the reported literatures were avoided.

Morphine and fentanyl are among the most used opioid drugs that confer analgesia and unwanted side effects through both G protein and arrestin signaling pathways of μ-opioid receptor (μOR). Here, we report structures of the human μOR-G protein complexes bound to morphine and fentanyl, which uncover key differences in how they bind the receptor. We also report structures of μOR bound to TRV130, PZM21, and SR17018, which reveal preferential interactions of these agonists with TM3 side of the ligand-binding pocket rather than TM6/7 side. In contrast, morphine and fentanyl form dual interactions with both TM3 and TM6/7 regions. Mutations at the TM6/7 interface abolish arrestin recruitment of μOR promoted by morphine and fentanyl. Ligands designed to reduce TM6/7 interactions display preferential G protein signaling. Our results provide crucial insights into fentanyl recognition and signaling of μOR, which may facilitate rational design of next-generation analgesics.

Hongjie Qian,1,2 Qian Chen,1,2 Liyu Liang,1,2 Yang Zou,1,2 Huahua Pu,1,2 Liang Xin,1,2 Rong Song,1,2 Tingting Li,1,2 Huijuan Zhu,1,2 Yu Wang,3 Guanghui Tian,4 Jingshan Shen,2,3 Hualiang Jiang,2,3 Chen Yu,1,2 Zhen Wang,2,3 Jingying Jia1,2 1Central Laboratory, Shanghai Xuhui Central Hospital, Shanghai, 200031, People’s Republic of China; 2Shanghai Engineering Research Center of Phase I Clinical Research & Quality Consistency Evaluation for Drugs, Shanghai, 200031, People’s Republic of China; 3CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People’s Republic of China; 4Vigonvita Life Science Co., Ltd., Suzhou, 215123, People’s Republic of ChinaCorrespondence: Jingying JiaShanghai Xuhui Central Hospital, No. 966, Huaihai Road(M), Shanghai, 200031, People’s Republic of ChinaTel/Fax +86 21 54030254Email jyjia@shxh-centerlab.comZhen WangShanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zu Chong Zhi Road, Pudong, Shanghai, 201203, People’s Republic of ChinaTel +86 21 20231000Fax +86 21 20231962Email wangzhen@simm.ac.cnPurpose: TPN171H is a novel, potent and selective phosphodiesterase type 5 (PDE5) inhibitor for the treatment of pulmonary arterial hypertension (PAH). The objective of this study was to evaluate the safety, tolerability, and pharmacokinetics of TPN171H in healthy subjects after single and multiple dosing, in addition, to investigate the food effect on pharmacokinetics and safety of TPN171H.Methods: The entire study was comprised of three parts: Part I (single ascending-dose study), Part II (food effect study), and Part III (multiple ascending-dose study). A total of 63 healthy subjects were enrolled in the study. TPN171H tablet or placebo was administered per protocol requirements. Blood samples were collected at the designated time points for pharmacokinetic analysis. Safety was assessed by clinical examinations and adverse events.Results: In Part I, AUC and Cmax were proved to be linear within the 5– 30 mg dose range. T1/2 of TPN171H was 8.02– 10.88 h. In Part II, we figured out that TPN171H administration under fed condition could decrease Cmax, prolong Tmax, but had no effect on AUC. In Part III, the accumulation ratio at steady-state for AUC and Cmax indicated that TPN171H has a slight accumulation upon repeated dosing. Subjects were generally tolerable after TPN171H administration. Compared with other PDE5 inhibitors, TPN171H was found to have no impact on blood pressure and color discrimination.Conclusion: TPN171H was safe and generally tolerated in healthy subjects. Based on the half-life, food effect, and safety profile of TPN171H, we recommend a once-daily, post-meal administration of TPN171H in subsequent clinical studies in healthy subjects and patients with PAH.Keywords: TPN171H, PDE5 inhibitor, safety, pharmacokinetics, food effect, healthy subjects

The ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) urgently needs an effective cure. 3CL protease (3CLpro) is a highly conserved cysteine proteinase that is indispensable for coronavirus replication, providing an attractive target for developing broad-spectrum antiviral drugs. Here we describe the discovery of myricetin, a flavonoid found in many food sources, as a non-peptidomimetic and covalent inhibitor of the SARS-CoV-2 3CLpro. Crystal structures of the protease bound with myricetin and its derivatives unexpectedly revealed that the pyrogallol group worked as an electrophile to covalently modify the catalytic cysteine. Kinetic and selectivity characterization together with theoretical calculations comprehensively illustrated the covalent binding mechanism of myricetin with the protease and demonstrated that the pyrogallol can serve as an electrophile warhead. Structure-based optimization of myricetin led to the discovery of derivatives with good antiviral activity and the potential of oral administration. These results provide detailed mechanistic insights into the covalent mode of action by pyrogallol-containing natural products and a template for design of non-peptidomimetic covalent inhibitors against 3CLpros, highlighting the potential of pyrogallol as an alternative warhead in design of targeted covalent ligands., SARS-CoV-2 3CL protease (3CLpro) is essential for coronavirus replication and of great interest as an antiviral drug target. Here, the authors show that the naturally occurring flavonoid myricetin is a non-peptidomimetic and covalent inhibitor of 3CLpro, and they solve crystal structures of 3CLpro with myricetin and derivatives, which reveal that the pyrogallol group covalently modifies the catalytic cysteine.

Herein we describe a focused set of new arylpiperazine derivatives as potential broad-spectrum antipsychotics. The general structure contains a quinolinone-like moiety, an arylpiperazine moiety, and a five-atom linker. Among them, 7-(5-(4-(benzo[d]isothiazol-4-yl)piperazin-1-yl)pentyl)quinolin-2(1H)-one (S6) shows a promising preclinical profile. Compound S6, characterized by partial D2 R agonism, 5-HT1A R agonism, 5-HT2A R antagonism, and blockade of SERT activities, was found to decrease psychosis- and depressive-like symptoms in rodents. The polypharmacological profile of S6 could provide opportunities for the treatment of various other central nervous system disorders such as anxiety, depression, and psychoses associated with dementia. Furthermore, S6 demonstrated acceptable safety, toxicology, and pharmacokinetic profiles, and has been selected as a preclinical candidate for further evaluation in schizophrenia.

Natural products (NPs), including traditional Chinese medicine (TCM), have been long and widely used in the prevention and treatment of central nervous system (CNS) diseases by virtue of their abundant sources, diverse structures, and novel activities. In this review article, we intend to summarize and discuss the situation or status of the clinical employments or trials of the NPs and their derivatives with CNS activities. NPs that have been extensively studied in preclinical research in recent years are also included. The compounds presented in this review are classified according to their indications and followed by details such as natural sources, possible biological mechanisms, and development status, while a considerable proportion of them are found in TCM. In addition, some drug combinations with synergistic effects are also mentioned. According to their impressive therapeutic effects and novel chemical structures, NPs are not only effective therapeutic remedies in clinic, but also lead compounds for structural modification, which indicate that nature brings new avenues to the therapy of CNS diseases.

Efforts toward route evaluation and process optimization for the preparation of brexpiprazole (1) are described. Starting from commercially available dihydroquinolinone 11, a three-step synthesis route composed of O-alkylation, oxidation, and N-alkylation was selected for industry-oriented process development aiming to reduce side reactions and achieve better impurity profiles. The reaction conditions of the three steps were investigated, and the control strategy for the process-related impurities was established. The optimized process was validated on the kilogram scale and now is viable for commercialization, with the results of not less than 99.90% purity of 1 (by HPLC) and not more than 0.05% of persistent impurities 15 and 16.

Favipiravir was first synthesized from an inexpensive and commercially available starting material, 2-aminopyrazine. The preferred route embedded within Scheme 4 consisted of seven steps, and was highlighted by the novel and efficient synthesis of 3,6-dichloropyrazine-2-carbonitrile 8. This intermediate was prepared in four successive steps which were regioselective chlorination of the pyrazine ring, bromination, Pd-catalyzed cyanation, and Sandmeyer diazotization/chlorination. This protocol eliminated the hazardous POCl3 of previous synthetic methods and offered a better yield (48%) which was 1.3-fold higher than a recently published procedure. From intermediate 8, the subsequent nucleophilic fluorination, nitrile hydration and hydroxyl substitution efficiently afforded the target product. Another synthetic approach with the same starting material was also investigated to bypass the allergy-causing dichloro intermediate 8. However, the key step of monofluorination at the pyrazine C6 position of intermediate 19 or 22 was not achieved.

The chemical modification of the primary amino groups of amino acid derivatives and peptides is an important process in the pharmaceutical industry and the field of chemical biology. However, suitable reactions that can be carried out under mild and environmentally friendly conditions are limited. We present a versatile method to selectively modify primary amino groups using novel dihydrooxazolo[3,2-a]quinoliniums in 1-butanol as solvent under mild and metal-free conditions. The application of this method to peptides with primary amino, secondary amino, amide, alcoholic hydroxyl, phenolic hydroxyl, disulfide bond, ester and cyano groups revealed that only the primary amino groups were selectively modified, suggesting that this method is compatible with other reactive moieties. We also demonstrated that the quinolylation of existing peptides affected peptide bioactivity and stability, indicating that the novel dihydrooxazolo[3,2-a]quinoliniums can be widely applied, especially in medicinal chemistry and chemical biology.

Pulmonary hypertension (PH) is a progressive and life-threatening disease with poor prognosis despite many advances in medical therapy over the past 20 years. Novel therapies which target on the underlying pathology of PH are still urgent to be met. TPN171H is a recently found new compound that exhibits potent pharmacological effects in PH via inhibiting phosphodiesterase type 5 (PDE-5). However, as one icariin derivative, the anti-inflammatory effects of TPN171H for treating PH are not clear. The present study was designed to investigate the therapeutical effect of TPN171H against inflammation in PH and reveal the underlying mechanism. Hypoxia and monocrotaline (MCT)-induced PH rat models were established, which were treated by oral administration of TPN171H (5, 25 mg/kg/d) or sildenafil (25 mg/kg/d). The right ventricle systolic pressure (RVSP), right ventricle hypertrophy index (RVHI) and vascular remodeling were measured. The results suggested that TPN171H significantly reduced RVSP and RVHI, and reversed pulmonary vascular remodeling in rats with both models. Furthermore, in in vivo and in vitro research, our data suggested that TPN171H remarkably suppressed cathepsin B-mediated NLRP3 inflammasome activation, which may contribute to its therapeutical function for PH.

Herein, we reported a convenient and cost efficient one-pot synthesis of molnupiravir from cytidine. This method utilized N,N-dimethylformamide dimethyl acetal (DMF-DMA) as an extraordinary protecting agent to achieve site specific esterification at 5’-hydroxyl group of the nucleoside easily, and afforded this promising drug candidate (purity up to 99%, HPLC a/a) in 70% overall yield without chromatography purification, which is superior to the existing methods in aspect of the yield, the cost and the operation, and shows great potential value for commercial production. Furthermore, this excellent protecting agent was also successfully used in the synthesis of remdesivr from its parent nucleoside with a high total yield (76%).

Human inflammatory disease, multiple sclerosis (MS), is a demyelinating disease of central nervous system (CNS). The experimental autoimmune encephalomyelitis (EAE) is the most commonly used as experimental model because of its key pathological features' approximation of MS. The interaction between complex elements in immune system and in the CNS determines the MS pathogenesis. However, there is no cure for MS and the treatment for MS still encounters great challenges. Thus, finding a more effective disease-modifying treatment is imminent. In the present study, we investigated whether 9,10-Anhydrodehydroartemisin (ADART), a compound derived from artemisinin, could decrease demyelination in EAE and the underlying mechanisms. In established EAE mice, 100 mg/kg 9,10-Anhydrodehydroartemisinin (ADART) effectively reduced CNS and peripheral immune system infiltration inflammatory cells including CD4

Pulmonary arterial hypertension (PAH) is a devastating disease that can lead to right ventricular failure and premature death. Although approved drugs have been shown to be safe and effective, PAH remains a severe clinical condition, and the long-term survival of patients with PAH is still suboptimal. Thus, potential therapeutic targets and new agents to treat PAH are urgently needed. In recent years, a variety of related pathways and potential therapeutic targets have been found, which brings new hope for PAH therapy. In this perspective, not only are the marketed drugs used to treat PAH summarized but also the recently developed novel pharmaceutical therapies currently in clinical trials are discussed. Furthermore, the advances in natural products as potential treatment for PAH are also updated.

In this paper, a series of artemisinin derivatives were synthesized and evaluated. Studies have shown that IFN-γ produced by Th1 CD4