Discovery of peptidomimetic spiropyrrolidine derivatives as novel 3CL inhibitors against SARS-CoV -2.

Given the high pathogenicity and rapid mutation rates of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it is imperative to sustain efforts in drug research and development. Herein, we present the design, synthesis, and evaluation of peptidomimetic spiropyrrolidine derivatives as potent 3CL inhibitors against SARS-CoV-2. Among the synthesized derivatives, several compounds exhibited high potency in inhibiting 3CL, with IC values ranging from 21 nM to 53 nM.

Synthesis and biological evaluation of multimodal monoaminergic arylpiperazine derivatives with potential antidepressant profile.

Depression is a common psychiatric disorder with an estimated global prevalence of 4.4 %. Here, we designed a series of new multimodal monoaminergic arylpiperazine derivatives using a pharmacophore hybrid approach and synthesized them for the treatment of depression.

Impurity study of tecovirimat.

This article delineates the systematic identification, synthesis, and impurity control methods used during the manufacturing process development of tecovirimat, an antiviral drug that treats monkeypox. Critical impurities were synthesized, and their chemical structure was confirmed through NMR analysis, GC, and HPLC mass spectrometry. The results established a thorough approach to identify, address, and control impurities to produce high-quality tecovirimat drug substance in accordance with International Conference on Harmonization (ICH)-compliant standards.

An Alternative Approach to Synthesize Sildenafil via Improved Copper-Catalyzed Cyclization.

A facile synthetic pathway for sildenafil has been developed. This approach is characterized by a ligand-free Ullmann-type copper-catalyzed coupling reaction to construct sildenafil and its derivative, pyrrazolo[4,3-]pyrimidin-7-one ring, with yields of 79% and 82%, respectively, in a convergent fashion by connecting key building blocks halo-pyrazole moiety with 2-ethoxybenzamidine and 2-ethoxy-5-[(4-methylpiperazin-1-yl)sulfonyl]benzamidine in a one-pot reaction. Thus, this approach circumvents the need to use nitric/sulfuric acid for nitration, a costly Pd-catalyst for reduction, and coupling agents encountered in the reported processes.

Improved and ligand-free copper-catalyzed cyclization for an efficient synthesis of benzimidazoles from -bromoarylamine and nitriles.

We present an improved copper-catalyzed cyclization for an efficient synthesis of benzimidazoles from -bromoarylamine and nitriles, under mild and ligand-free conditions. The optimal conditions yielded exceptional products of up to 98%, demonstrating the broad applicability of this synthetic strategy in generating a wide range of valuable imidazole derivatives. This methodology enables the efficient synthesis of various substituted benzimidazole derivatives and offers an environmentally friendly alternative to conventional methods.

Glimepiride, a novel soluble epoxide hydrolase inhibitor, protects against heart failure via increasing epoxyeicosatrienoic acids.

Background: Epoxyeicosatrienoic acids (EETs), which exert multiple endogenous protective effects, are hydrolyzed into less active dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase (sEH). However, commercial drugs related to EETs or sEH are not yet in clinical use.

Methods: Firstly, the plasma concentration of EETs and DHETs of 316 patients with heart failure (HF) were detected and quantitated by liquid chromatography-tandem mass spectrometry.

Structure-based development and preclinical evaluation of the SARS-CoV-2 3C-like protease inhibitor simnotrelvir.

The persistent pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants accentuates the great demand for developing effective therapeutic agents. Here, we report the development of an orally bioavailable SARS-CoV-2 3C-like protease (3CL) inhibitor, namely simnotrelvir, and its preclinical evaluation, which lay the foundation for clinical trials studies as well as the conditional approval of simnotrelvir in combination with ritonavir for the treatment of COVID-19. The structure-based optimization of boceprevir, an approved HCV protease inhibitor, leads to identification of simnotrelvir that covalently inhibits SARS-CoV-2 3CL with an enthalpy-driven thermodynamic binding signature.

Pharmacokinetics, mass balance, and metabolism of [C]TPN171, a novel PDE5 inhibitor, in humans for the treatment of pulmonary arterial hypertension.

TPN171 is a novel phosphodiesterase-5 (PDE5) inhibitor used to treat pulmonary arterial hypertension (PAH) and erectile dysfunction (ED), which currently is undergoing phase II clinical trials in China. In this single-center, single-dose, nonrandomized, and open design study, radiolabeled [C]TPN171 was used to investigate the metabolic mechanism, pharmacokinetic characteristics, and clearance pathways of TPN171 in 6 healthy Chinese male volunteers. Each volunteer was administered a single oral suspension of 10 mg (100 μCi) of [C]TPN171.

SARS-CoV-2 envelope protein causes acute respiratory distress syndrome (ARDS)-like pathological damages and constitutes an antiviral target.

Cytokine storm and multi-organ failure are the main causes of SARS-CoV-2-related death. However, the origin of excessive damages caused by SARS-CoV-2 remains largely unknown. Here we show that the SARS-CoV-2 envelope (2-E) protein alone is able to cause acute respiratory distress syndrome (ARDS)-like damages in vitro and in vivo.

TPN672: A Novel Serotonin-Dopamine Receptor Modulator for the Treatment of Schizophrenia.

TPN672 [7-(2-(4-(benzothiophen-4-yl) piperazin-1-yl)ethyl)quinolin-2(1H)-one maleate] is a novel antipsychotic candidate with high affinity for serotonin and dopamine receptors that is currently in clinical trial for the treatment of psychiatric disorders. In vitro binding study showed that TPN672 exhibited extremely high affinity for serotonin 1A receptor (5-HTR) ( = 0.23 nM) and 5-HTR ( = 2.

Synthesis and biological investigation of triazolopyridinone derivatives as potential multireceptor atypical antipsychotics.

A series of triazolopyridinone derivatives originating from the antidepressant trazodone was designed and pharmacologically evaluated. Most of the compounds with a multireceptor functional profile exhibited high potency at the D, 5-HT, and 5-HT receptors. Compounds S1, S3, S9 and S12 were selected for further evaluation of druggable potential.

Synthesis and Biological Evaluation of Five-Atom-Linker-Based Arylpiperazine Derivatives with an Atypical Antipsychotic Profile.

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.

Oxidative Aromatization of 3,4-Dihydroquinolin-2(1 H)-ones to Quinolin-2(1 H)-ones Using Transition-Metal-Activated Persulfate Salts.

Inorganic persulfate salts were identified as efficient reagents for the oxidative aromatization of 3,4-dihydroquinolin-2(1 H)-ones through the activation of readily available transition metals, such as iron and copper. The feasible protocol conforming to the requirement of green chemistry was utilized in the preparation of the key intermediate (7-(4-chlorobutoxy)quinolin-2(1 H)-one 2) of brexpiprazole in 80% isolated yield on a 100 g scale, and different quinolin-2(1 H)-one derivatives with various functional groups were demonstrated in 52-89% yields.

Continuation of structure-activity relationship study of novel benzamide derivatives as potential antipsychotics.

A series of benzamide derivatives possessing potent dopamine D , serotonin 5-HT , and 5-HT receptor properties were synthesized and evaluated as potential antipsychotics. Among them, 5-(4-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)butoxy)-N-cyclopropyl-2-fluorobenzamide (4k) held the best pharmacological profile. It not only exhibited potent and balanced activities for the D , 5-HT , and 5-HT receptors, but was also endowed with low to moderate activities for the 5-HT , H , and M receptors, suggesting a low propensity for inducing weight gain or diabetes.

Synthesis and biological evaluation of a series of novel pyridinecarboxamides as potential multi-receptor antipsychotic drugs.

In previous study, a series of benzamides was identified as potent antipsychotic agents. As a continuation of the program to discover novel antipsychotics, herein we reported the evaluation of a series of pyridinecarboxamide derivatives. The most promising compound 7h not only held good activities on dopamine D, serotonin 5-HT and 5-HT receptors, but also exhibited low potency for α, H and 5-HT receptors, indicating a low propensity of side effects like orthostatic hypotension and weight gain.

Synthesis and biological evaluation of a series of multi-target N-substituted cyclic imide derivatives with potential antipsychotic effect.

In the present study, a series of multi-target N-substituted cyclic imide derivatives which possessed potent dopamine D, serotonin 5-HT and 5-HT receptors properties were synthesized and evaluated as potential antipsychotics. Among these compounds, (3aR,4R,7S,7aS)-2-(4-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)butyl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione hydrochloride (3d) held a promising pharmacological profile. 3d not only showed potent and balanced in vitro activities on D/5-HT/5-HT receptors, but also endowed with low to moderate activities on 5-HT, H, α, M receptors and hERG channel, suggesting a low liability to induce side effects such as weight gain, orthostatic hypotension and QT prolongation.

Synthesis and biological investigation of tetrahydropyridopyrimidinone derivatives as potential multireceptor atypical antipsychotics.

In the present study, a series of tetrahydropyridopyrimidinone derivatives, possessing potent dopamine D, serotonin 5-HT and 5-HT receptors properties, was synthesized and evaluated as potential antipsychotics. Among them, 3-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (10d) held the best pharmacological profile. It not only exhibited potent and balanced activities for D, 5-HT, and 5-HT receptors, but was also endowed with low activities for α, 5-HT, H receptors and hERG channels, suggesting a low propensity for inducing orthostatic hypotension, weight gain and QT prolongation.

[Research progress of antipsychotics].

Epidemiology indicates that schizophrenia affects approximately 8‰ of the world’s population. The atypical (second and third generation) antipsychotics generally endowed with D(2)/5-HT(2A) receptors antagonism properties are commonly used as first-line drugs for the treatment of schizophrenia presently. They have been proven effective in the treatment of positive and negative symptoms of schizophrenia, but they are largely ineffective in the treatment of cognitive deficit.

Synthesis, structure-activity relationships, and biological evaluation of a series of benzamides as potential multireceptor antipsychotics.

In the present study, a series of benzamides, endowed with potent dopamine D2, serotonin 5-HT1A and 5-HT2A receptors properties, was synthesized and evaluated as potential antipsychotics. Among them, 3-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl)butoxy)-N-methylbenzamide (21) and its fluoro-substituted analogue (22) held the best pharmacological binding profiles. They not only presented potent activities for D2, 5-HT1A, and 5-HT2A receptors, but were also endowed with low activities for 5-HT2C, H1 receptors and hERG channels, suggesting a low propensity of inducing weight gain and QT prolongation.