Suitable Pharmacokinetic Profile Research Articles

Synthesis, structure analysis, biological activity evaluation and pharmacological aspects prediction of two newly synthesized compounds: N-methylbenzylammonium bromide and 2-amino-5-ammoniopyridinium dichloride

Medical and pharmaceutical demands have driven the development of new synthetic materials. This study explores bioinspired materials from various intriguing biological compositions, focusing on functional and structural categories. In this context, two novel salts, (C8H12N),Br (I) and (C5H9N3),2Cl (II) were synthesized via slow evaporation at ambient temperature and characterized using multiple techniques. Their crystal packing is stabilized by non-covalent interactions, including N–H…Br, C–H…Br, C–H…Cl and N–H…Cl hydrogen bonds. Three-dimensional Hirshfeld surface analysis followed by two-dimensional fingerprint plots provides insights into the intermolecular interactions within the crystalline structure. The thermal decomposition of the compounds was analyzed using TGA-DTA techniques. The synthesized products were also evaluated for in vitro antifungal, antioxidant and antibacterial activities, revealing notable antioxidant properties. Additionally, molecular docking studies were conducted against the bacterial DNA gyrase of Staphylococcus aureus, Listeria monocytogenes, Salmonella enterica Typhimurium and Pseudomonas aeruginosa as well as the fungal chitin synthase enzyme of Aspergillus niger and Fusarium oxysporum. Based on the obtained free energies of binding (ΔG), compounds I and II demonstrated significant effects against the tested microorganisms by disrupting the topological state of bacterial genetic material and inhibiting fungal chitin formation. ADME (Absorption, Distribution, Metabolism and Excretion) prediction using SwissADME webserver suggest that these compounds have suitable pharmacokinetic profiles and could serve as promising drug candidates against various microbial infections.

Anti-colorectal Cancer Activity of Quinazoline Derivatives: A Comprehensive Review

Introduction and Objective: The identification of a bioactive template (or lead) is one of the important features of modern drug discovery. Natural products, synthetic and biotechnological sources, serve as important templates for the development of novel bioactive molecules. Quinazoline is one of the heterocyclic templates present in many natural and synthetic drugs and exhibits various biological activities, including anticancer, by blocking the pharmacological pathway of different targets. Methodology: In this study, the data was collected from the literature and patents to examine the anticolorectal cancer efficacy of quinazoline compounds and their mechanism of actions. According to the published literature and patents, the benzene and/or pyrimidine rings of the quinazoline have been substituted with amino groups or substituted amino groups to develop novel analogues endowed with anticancer properties. The anti-colorectal cancer activity of quinazolines was due to the flexible chain containing terminal phenyl and/or heterocyclic rings (thiazole, pyrazole, piperidine, piperazine, etc.). Results: These quinazoline derivatives were found to inhibit the growth of colorectal cancer cells by modulating the expression of specific genes and proteins involved in cancer progression, such as receptor tyrosine kinases, epidermal growth factor receptors, dihydrofolate reductase, topoisomerases, histone deacetylase, and apoptotic proteins. Conclusion: These findings suggest that the quinazoline nucleus may be exploited to identify new anticolorectal cancer agents with suitable pharmacokinetic profiles.

Evaluation of Pharmacokinetic and Pharmacodynamic (PK/PD) of Novel Fluorenylmethoxycarbonyl- Phenylalanine Antimicrobial Agent.

To assess the pharmacokinetic profile, in-vivo toxicity, and efficacy of 9-Fluorenylmethoxycarbonyl-L-phenylalanine (Fmoc-F) as a potential antibacterial agent, with a focus on its suitability for clinical translation. An RP-HPLC-based bio-analytical method was developed and qualified to quantify Fmoc-F levels in mouse plasma for pharmacokinetic analysis. Oral bioavailability was determined, and in-vivo toxicity was evaluated following intra-peritoneal administration. Efficacy was assessed by measuring the reduction in Staphylococcus aureus burden and survival rates in BALB/c mice. The RP-HPLC method is highly sensitive, detecting as low as 0.8µgmL-1 (~ 2µM) of Fmoc-F in blood plasma. This study revealed that Fmoc-F has an oral bioavailability of 65 ± 18% and suitable pharmacokinetic profile. Further, we showed that intra-peritoneal administration of Fmoc-F is well tolerated by BALB/c mice and Fmoc-F treatment (100mg/kg, i.p.) significantly reduces Staphylococcus aureus burden from visceral organs in BALB/c mice but falls short in enhancing survival rates at higher bacterial loads. The study provides crucial insights into the pharmacokinetic and pharmacodynamic properties of Fmoc-F. The compound displayed favourable oral bioavailability and in-vivo tolerance. Its significant reduction of bacterial burden underscores its potential as a treatment for systemic infections. However, limited effectiveness for severe infections, short half-life, and inflammatory response at higher doses need to be addressed for its clinical application.

Fluoropropanoic Acid Compound Revealed as Novel Macrophage Migration Inhibitory Factor (MIF) Inhibitor through Virtual Screening and Molecular Dynamics (MD) Simulation

Introduction: Macrophage Migration Inhibitory Factor (MIF), a cytokine that signals for inflammatory response, has been implicated in multiple inflammatory disorders, including RA. Inhibition of MIF activity by anti-MIF inhibitors can lead to improved prognosis and increased quality of life. Development of a medically viable MIF inhibitor has been pursued without success, and no inhibitor that binds to MIF active site has been approved as a drug. Current treatments of Rheumatoid Arthritis (RA), an inflammatory disorder driven by an autoimmune response, target pain management and control of progression, but the risk of toxicity and increased side effects lead to limited success. Methods: Our goal was to search for drug-like lead compounds that bind more potently to MIF active sites than current inhibitors. We selected ten classes of chemical compounds that have previously shown in vitro MIF inhibitory activity and screened ~47,000 compounds belonging to these classes through virtual docking, alongside ~900,000 compounds from ZINC and TCM (Traditional Chinese Medicine) databases. The ligands with the higher energy of binding than current inhibitors were analyzed for ADMET profiles and drug-likeness properties. Results: In total, 75 ligands showed binding energies higher than the threshold of -7.5 kcal/mol, and 5 lead compounds were identified with suitable pharmacokinetic profiles and drug-like characteristics. Among them, molecular dynamics simulation showed a stable ligand-protein complex for 3-[3-fluoro-4- (trifluoromethyl)phenyl] propanoic acid. Conclusion: With the identification of this lead compound, new opportunities can be sought in the pursuit of a novel treatment for Rheumatoid Arthritis.

New Antibiotics for the Treatment of Nosocomial Central Nervous System Infections.

Nosocomial central nervous system (CNS) infections with carbapenem- and colistin-resistant Gram-negative and vancomycin-resistant Gram-positive bacteria are an increasing therapeutic challenge. Here, we review pharmacokinetic and pharmacodynamic data and clinical experiences with new antibiotics administered intravenously for the treatment of CNS infections by multi-resistant bacteria. Cefiderocol, a new siderophore extended-spectrum cephalosporin, pharmacokinetically behaves similar to established cephalosporins and at high doses will probably be a valuable addition in our therapeutic armamentarium for CNS infections. The new glycopeptides dalbavancin, telavancin, and oritavancin are highly bound to plasma proteins. Although effective in animal models of meningitis, it is unlikely that they reach effective cerebrospinal fluid (CSF) concentrations after intravenous administration alone. The β-lactam/β-lactamase inhibitor combinations have the principal problem that both compounds must achieve adequate CSF concentrations. In the commercially available combinations, the dose of the β-lactamase inhibitor tends to be too low to achieve adequate CSF concentrations. The oxazolidinone tedizolid has a broader spectrum but a less suitable pharmacokinetic profile than linezolid. The halogenated tetracycline eravacycline does not reach CSF concentrations sufficient to treat colistin-resistant Gram-negative bacteria with usual intravenous dosing. Generally, treatment of CNS infections should be intravenous, whenever possible, to avoid adverse effects of intraventricular therapy (IVT). An additional IVT can overcome the limited penetration of many new antibiotics into CSF. It should be considered for patients in which the CNS infection responds poorly to systemic antimicrobial therapy alone.

Sequential rearrangement and stereochemical reorganization to design an antimicrobial peptide with enhanced stability

Antimicrobial peptides (AMPs) are natural molecules that function within the innate immune system to counteract pathogenic invasion and minimize the detrimental consequences of infection. However, utilizing these molecules for medical applications has been challenging. In this study, we selected a model AMP with poor stability, Tilapia Piscidin 4 (TP4), and modified its sequence and chirality (TP4-γ) to improve its potential for clinical application. The strategy of chirality inversion was inspired by the cereulide peptide, which has a DDLL enantiomer pattern and exhibits exceptional stability. Sequential substitution of key residues and selective chirality inversion yielded a less toxic peptide with enhanced stability and notable antimicrobial activity. In addition to its superior stability profile and antimicrobial activity, TP4-γ treatment reduced the level of LPS-induced nitric oxide (NO) release in a macrophage cell line. This reduction in NO release may reflect anti-inflammatory properties, as NO is widely known to promote inflammatory processes. Hence, our heterochiral peptide construct shows a more suitable pharmacokinetic profile than its parental compound, and further studies are warranted to develop the molecule for potential clinical application.

CONFORMATIONAL STUDY OF MOLECULES IN A BIOLOGICAL ENVIRONMENT, DESIGN OF INHIBITORS OF HUMAN AMINOPEPTIDASE M1 IMPLICATED IN CANCER THERAPY

Objective: A novel subnanomolar anticancer hydroxamic acid containing drug candidates, inhibitors of human M1 aminopeptidase (APN) a recent validated target and has reached the predicted subnanomolar range of inhibitory potency. Methods: A quantitative structure activity relationships (QSAR) complexation model has been developed from a compounds of 37 hydroxamic acid derivatives (AHD1-37 as training set, TS) to establish a linear correlation between the calculated relative Gibbs free energies (GFE: ΔΔGcom) of APN-AHDx complex formation and the experimental inhibition potency (Kiexp). The predictive power of the QSAR model was then validated first with 9 other AHDs not included in the TS and thereafter with the generation of a 3D-QSAR-PH4 pharmacophore (PH4) model to screen the AHD chemical subspace built as a virtual combinatorial library of more than 58,644 AHD analogs). Finally the best PH4 hits were evaluated with the initial QSAR model for predicted potency (Kipre) and pharmacokinetic profile. Results: The QSAR model linear correlation equation: pKiexp=-0.1901×∆∆Gcom + 8.2886 , R2=0.94, the subsequent PH4 model linear correlation between experiment and PH4-estimated Ki: pKiexp=1.0006× pKipre + 0.0028, R2=0.79 documents the high predictive power of this approach. Finally the screening of the virtual library of AHD analogs yielded 95 orally bioavailable candidates the best reaching a predicted potency (Kipre) of 50 pM and displaying favorable pharmacokinetic profile. Conclusion: The combined use of molecular modeling (QSAR) and in silico PH4-based screening of the hypothetical combinatorial library has resulted in proposed and predicted potent anticancer candidates with a suitable pharmacokinetic profile. Peer Review History: Received: 3 August 2023; Revised: 12 September; Accepted: 25 October, Available online: 15 November 2023 Academic Editor: Dr. Nuray Arı, Ankara University, Turkiye, ari@ankara.edu.tr Received file: Reviewer's Comments: Average Peer review marks at initial stage: 7.0/10 Average Peer review marks at publication stage: 9.0/10 Reviewers: Prof. Hassan A.H. Al-Shamahy, Sana'a University, Yemen, shmahe@yemen.net.ye Prof. Dr. A. Hakan AKTAŞ, Süleyman Demirel University, Faculty of Science and Art, Department of Chemistry, Isparta-Turkey, hakanaktas@sdu.edu.tr

Evaluation of Pharmacokinetic Feasibility of Febuxostat/L-pyroglutamic Acid Cocrystals in Rats and Mice.

Febuxostat (FBX), a selective xanthine oxidase inhibitor, belongs to BCS class II, showing low solubility and high permeability with a moderate F value (<49%). Recently, FBX/L-pyroglutamic acid cocrystal (FBX-PG) was developed with an improving 4-fold increase of FBX solubility. Nevertheless, the in vivo pharmacokinetic properties of FBX-PG have not been evaluated yet. Therefore, the pharmacokinetic feasibility of FBX in FBX- and FBX-PG-treated rats and mice was compared in this study. The results showed that the bioavailability (F) values of FBX were 210% and 159% in FBX-PG-treated rats and mice, respectively. The 2.10-fold greater total area under the plasma concentration-time curve from time zero to infinity (AUC0-inf) of FBX was due to the increased absorption [i.e., 2.60-fold higher the first peak plasma concentration (Cmax,1) at 15 min] and entero-hepatic circulation of FBX [i.e., 1.68-fold higher the second peak plasma concentration (Cmax,2) at 600 min] in FBX-PG-treated rats compared to the FBX-treated rats. The 1.59-fold greater AUC0-inf of FBX was due to a 1.65-fold higher Cmax,1 at 5 min, and a 1.15-fold higher Cmax,2 at 720 min of FBX in FBX-PG-treated mice compared to those in FBX-treated mice. FBX was highly distributed in the liver, stomach, small intestine, and lungs in both groups of mice, and the FBX distributions to the liver and lungs were increased in FBX-PG-treated mice compared to FBX-treated mice. The results suggest the FBX-PG has a suitable pharmacokinetic profile of FBX for improving its oral F value.

Potent Dual Inhibitors of Steroid Sulfatase and 17β-Hydroxysteroid Dehydrogenase Type 1 with a Suitable Pharmacokinetic Profile for In Vivo Proof-of-Principle Studies in an Endometriosis Mouse Model.

Treating estrogen-dependent diseases like endometriosis with drugs suppressing local estrogen activation may be superior to existing endocrine therapies. Steroid sulfatase (STS) and 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) are key enzymes of local estrogen activation. We describe the rational design, synthesis, and biological profilation of furan-based compounds as a novel class of dual STS/17β-HSD1 inhibitors (DSHIs). In T47D cells, compound 5 showed irreversible inhibition of STS and potent, reversible inhibition of 17β-HSD1. It was selective over 17β-HSD2 and displayed high metabolic stabilities in human and mouse liver S9 fractions. No effect on cell viability was detected up to 31 μM (HEK293) and 23 μM (HepG2), respectively, and there was no activation of the aryl hydrocarbon receptor (AhR) up to 3.16 μM. Single daily application to mice revealed steady-state plasma levels high enough to make this compound eligible for an in vivo proof-of-principle study in a mouse endometriosis model.

First-in-Human Study of the Radioligand 68Ga-N188 Targeting Nectin-4 for PET/CT Imaging of Advanced Urothelial Carcinoma.

Nectin-4 is an emerging biomarker for cancer diagnosis and therapy. Recently, enfortumab vedotin (EV) was approved by the FDA as the first nectin-4 targeting antibody-drug conjugate for treating advanced urothelial carcinoma (UC). A PET imaging method to noninvasively quantify nectin-4 expression level would potentially help to select patients most likely to respond to EV and predict the response. In this study, we designed a bicyclic peptide-based nectin-4 targeting radiotracer 68Ga-N188. Initially, we performed preclinical evaluations of 68Ga-N188 in UC cell lines and xenograft mouse models. Next, we performed the translational study in healthy volunteers and a pilot cohort of patients with advanced UC on uEXPLORER total-body PET/CT. In the preclinical study, 68Ga-N188 showed high affinity to nectin-4, specific uptake in a nectin-4(+) xenograft mouse model, and suitable pharmacokinetic and safety profiles. In the translational study, 2 healthy volunteers and 14 patients with advanced UC were enrolled. The pharmacokinetic profile was determined for 68Ga-N188, and the nectin-4 relative expression level in different organs was quantitatively imaged. A clear correlation between PET SUV value and nectin-4 expression was observed, supporting the application of 68Ga-N188 PET as a companion diagnostic tool for optimizing treatments that target nectin-4. See related commentary by Jiang et al., p. 3259.

Design and preclinical evaluation of a novel apelin-based PET radiotracer targeting APJ receptor for molecular imaging of angiogenesis

APJ has been extensively described in the pathophysiology of angiogenesis and cell proliferation. The prognostic value of APJ overexpression in many diseases is now established. This study aimed to design a PET radiotracer that specifically binds to APJ. Apelin-F13A-NODAGA (AP747) was synthesized and radiolabeled with gallium-68 ([68Ga]Ga-AP747). Radiolabeling purity was excellent (> 95%) and stable up to 2 h. Affinity constant of [67Ga]Ga-AP747 was measured on APJ-overexpressing colon adenocarcinoma cells and was in nanomolar range. Specificity of [68Ga]Ga-AP747 for APJ was evaluated in vitro by autoradiography and in vivo by small animal PET/CT in both colon adenocarcinoma mouse model and Matrigel plug mouse model. Dynamic of [68Ga]Ga-AP747 PET/CT biodistributions was realized on healthy mice and pigs for two hours, and quantification of signal in organs showed a suitable pharmacokinetic profile for PET imaging, largely excreted by urinary route. Matrigel mice and hindlimb ischemic mice were submitted to a 21-day longitudinal follow-up with [68Ga]Ga-AP747 and [68Ga]Ga-RGD2 small animal PET/CT. [68Ga]Ga-AP747 PET signal in Matrigel was significantly more intense than that of [68Ga]Ga-RGD2. Revascularization of the ischemic hind limb was followed by LASER Doppler. In the hindlimb, [68Ga]Ga-AP747 PET signal was more than twice higher than that of [68Ga]Ga-RGD2 on day 7, and significantly superior over the 21-day follow-up. A significant, positive correlation was found between the [68Ga]Ga-AP747 PET signal on day 7 and late hindlimb perfusion on day 21. We developed a new PET radiotracer that specifically binds to APJ, [68Ga]Ga-AP747 that showed more efficient imaging properties than the most clinically advanced tracer of angiogenesis, [68Ga]Ga-RGD2.

Molecular Modeling, Virtual Screening, and Molecular Dynamics for Leishmania infantum Methionyl-tRNA Synthetase.

Visceral leishmaniasis is a neglected tropical disease (NTD) caused by Leishmania infantum and L. donovani that is lethal in cases of nontreatment. The treatments are limited by serious drawbacks involving safety, resistance, stability, and high costs. In this work, we aimed to identify inhibitors of Leishmania infantum methionyl-tRNA synthetase (LiMetRS), a validated molecular target for leishmaniasis drug discovery, using a combination of strategies. A virtual database of compounds was organized by filtering compounds from the ZINC15 database. Homology modeling was used to obtain the structure of LiMetRS based on the crystal coordinates of the enzyme from Trypanosoma brucei (TbMetRS). A virtual screening using molecular docking identified 10 candidate compounds from among more than 5 million that were included in the initial database. The selected hits were further evaluated using a script created in this work to select only the ligands that interacted with specific amino acids in the catalytic site of the enzyme. Furthermore, suitable pharmacokinetic profiles were predicted for the selected compounds, especially a good balance between aqueous solubility and lipophilic character, no ability to cross the blood-brain barrier, good oral absorption, and no liability toward P-gp efflux for most compounds. Six compounds were then subjected to all-atom molecular dynamics. Two compounds showed good stability when bound to the leishmanial enzyme, which provided a deeper understanding of the structural differences between TbMetRS and LiMetRS that can guide further drug discovery efforts for visceral leishmaniasis.

Results From a Multiple Ascending Dose Study in Healthy Volunteers of ACD856, a Positive Modulator of Neurotrophin Trk‐Receptors

AbstractBackgroundACD856 is a novel positive allosteric modulator of Trk‐receptors in clinical development for the treatment of Alzheimer’s disease and other disorders where cognition is impaired. The aim of this study was to assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of multiple ascending doses of ACD856.Method24 healthy volunteer subjects were administered ACD856 or placebo as a daily oral solution over 7 days in 3 cohorts of stepwise ascending doses. After each dose, the safety, tolerability, and pharmacokinetics of ACD856 were assessed by an internal Safety Review Committee to decide on the escalation of dose to the next cohort.ResultThere were no clinically significant changes from baseline in mean ECG, vital signs, physical examination findings, clinical chemistry, haematology, coagulation, or urinalysis parameters after receiving the 7 daily doses of ACD856. Occasional individual abnormal laboratory values were observed but all were assessed as not clinically significant. Most of the reported adverse events were of mild intensity, only a few were of moderate intensity and none of severe intensity. No serious adverse events were reported.The pharmacokinetic data confirmed the findings from the previously performed single ascending dose (SAD) study, including that ACD856 has a rapid absorption, long half‐life, high bioavailability, and a linear dose‐dependent exposure. The Cmax at steady state was approximately 1.6‐fold higher than the initial dose administration and no time‐dependent clearance was observed. Moreover, initial CSF data confirms CNS exposure of ACD856. Further PK, CSF and pharmacodynamic data will be shown at the time of presentation.ConclusionACD856 was shown to be safe and well tolerated in man at the tested dose levels and with a suitable pharmacokinetic profile for further clinical development. In the next step, ACD856 will be evaluated in a phase Ib study with the aim to further assess pharmacodynamic effects.

Design and Synthesis of a 2-Amino-pyridine Derivative as a Potent CDK8 Inhibitor for Anti-colorectal Cancer Therapy.

CDK8 is a transcriptional cyclin-dependent kinase and considered as a potential target in colon cancer therapeutics. Here, a novel selective CDK8 inhibitor was identified against colon cancer in vivo. Specifically, based on the structural information of the sorafenib-bound CDK8 structure, a series of novel 2-amino-pyridine derivatives were designed, synthesized, and evaluated. Among them, compound 29 showed strong inhibitory activity against CDK8 with an IC50 value of 46 nM and favorable selectivity. And there is an apparent interaction between the endogenous or overexpressed CDK8 and biotinylated-29. This compound exhibited antiproliferation potency on colon cancer cell lines with a high CDK8 expression level, suppressed the activation of WNT/β-catenin and transcriptional activity of the TCF family, and induced G1 phase arrested in HCT-116 cells. In addition, this compound showed potent activity against sorafenib-resistant HCT-116 cells. What's more, it exhibited low toxicity and suitable pharmacokinetic (PK) profiles and showed preferable antitumor effects in vivo.

The Prediction of Pharmacokinetic Properties of Compounds in &lt;i&gt;Hemigraphis alternata&lt;/i&gt; (Burm.F.) T. Ander Leaves Using pkCSM

The inflammatory process aids in healing and maintains the body's balance. Untreated acute inflammation can cause organ disease, which can lead to a chronic inflammatory phenotype. Hemigraphis alternata is a plant that has anti-inflammatory activity. The compounds contained in H. alternata leaves have been predicted to have an affinity for receptors involved in the inflammatory process. A large number of drug candidates were withdrawn from preclinical trials due to their poor pharmacokinetic profiles. Drug compounds must cross the barriers that exist in the body to reach their biological targets so that they can generate a biological effect. The pharmacokinetic features of 22 components in H. alternata leaves were predicted in order to search for inflammatory medication candidates with suitable pharmacokinetic profiles. The pkCSM, a strategy for predicting and optimizing the pharmacokinetic properties of small molecules based on distance-based graph signatures was used in this work. The pkCSM employed 20 predictors separated into four groups: absorption, distribution, metabolism, and excretion. Based on the prediction findings, there are five substances with the best pharmacokinetic features, 8a-methyl-3,4,4a,5,6,7-hexahydro-2H-naphthalene-1,8-dione, (E)-3,7,11,15-tetramethylhexadec-2-en-1-ol, 2-methylenecholestan-3-ol, 5-(hydroxymethyl) furan-2-carbaldehyde and 2,3-dihydro-2,5-dimethyl-5H-1,4-dioxepin.

Design and Synthesis of Novel Epigenetic Inhibitors Targeting Histone Deacetylases, DNA Methyltransferase 1, and Lysine Methyltransferase G9a with In Vivo Efficacy in Multiple Myeloma.

Concomitant inhibition of key epigenetic pathways involved in silencing tumor suppressor genes has been recognized as a promising strategy for cancer therapy. Herein, we report a first-in-class series of quinoline-based analogues that simultaneously inhibit histone deacetylases (from a low nanomolar range) and DNA methyltransferase-1 (from a mid-nanomolar range, IC50 < 200 nM). Additionally, lysine methyltransferase G9a inhibitory activity is achieved (from a low nanomolar range) by introduction of a key lysine mimic group at the 7-position of the quinoline ring. The corresponding epigenetic functional cellular responses are observed: histone-3 acetylation, DNA hypomethylation, and decreased histone-3 methylation at lysine-9. These chemical probes, multitarget epigenetic inhibitors, were validated against the multiple myeloma cell line MM1.S, demonstrating promising in vitro activity of 12a (CM-444) with GI50 of 32 nM, an adequate therapeutic window (>1 log unit), and a suitable pharmacokinetic profile. In vivo, 12a achieved significant antitumor efficacy in a xenograft mouse model of human multiple myeloma.

Development of a ghrelin receptor inverse agonist for positron emission tomography.

Imaging of Ghrelin receptors in vivo provides unique potential to gain deeper understanding on Ghrelin and its receptors in health and disease, in particular, in cancer. Ghrelin, an octanoylated 28-mer peptide hormone activates the constitutively active growth hormone secretagogue receptor type 1a (GHS-R1a) with nanomolar activity. We developed novel compounds, derived from the potent inverse agonist K-(D-1-Nal)-FwLL-NH2 but structurally varied by lysine conjugation with 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA), palmitic acid and/or diethylene glycol (PEG2) to allow radiolabeling and improve pharmacokinetics, respectively. All compounds were tested for receptor binding, potency and efficacy in vitro, for biodistribution and -kinetics in rats and in preclinical prostate cancer models on mice. Radiolabeling with Cu-64 and Ga-68 was successfully achieved. The Cu-64- or Ga-68-NODAGA-NH-K-K-(D-1-NaI)-F-w-L-L-NH2 radiotracer were specifically accumulated by the GHS-R1a in xenotransplanted human prostate tumor models (PC-3, DU-145) in mice. The tumors were clearly delineated by PET. The radiotracer uptake was also partially blocked by K-(D-1-Nal)-FwLL-NH2 in stomach and thyroid. The presence of the GHS-R1a was also confirmed by immunohistology. In the arterial rat blood plasma, only the original compounds were found. The Cu-64 or Ga-68-NODAGA-NH-K-K-(D-1-NaI)-F-w-L-L-NH2 radiolabeled inverse agonists turned out to be potent and safe. Due to their easy synthesis, high affinity, medium potency, metabolic stability, and the suitable pharmacokinetic profiles, they are excellent tools for imaging and quantitation of GHS-R1a expression in normal and cancer tissues by PET. These compounds can be used as novel biomarkers of the Ghrelin system in precision medicine.

Development of versatile and potent monoquaternary reactivators of acetylcholinesterase.

To date, the only treatments developed for poisoning by organophosphorus compounds, the most toxic chemical weapons of mass destruction, have exhibited limited efficacy and versatility. The available causal antidotes are based on reactivation of the enzyme acetylcholinesterase (AChE), which is rapidly and pseudo-irreversibly inhibited by these agents. In this study, we developed a novel series of monoquaternary reactivators combining permanently charged moieties tethered to position 6- of 3-hydroxypyridine-2-aldoxime reactivating subunit. Highlighted representatives (21, 24, and 27; also coded as K1371, K1374, and K1375, respectively) that contained 1-phenylisoquinolinium, 7-amino-1-phenylisoquinolinium and 4-carbamoylpyridinium moietiesas peripheral anionic site ligands, respectively, showed efficacy superior or comparable to that of the clinically used standards. More importantly, these reactivators exhibited wide-spectrum efficacy and were minutely investigated via determination of their reactivation kinetics in parallel with molecular dynamics simulations to study their mechanisms of reactivation of the tabun-inhibited AChE conjugate. To further confirm the potential applicability of these candidates, a mouse in vivo assay was conducted. While K1375 had the lowest acute toxicity and the most suitable pharmacokinetic profile, the oxime K1374 with delayed elimination half-life was the most effective in ameliorating the signs of tabun toxicity. Moreover, both in vitro and in vivo, the versatility of the agents was substantially superior to that of clinically used standards. Their high efficacy and broad-spectrum capability make K1374 and K1375 promising candidates that should be further investigated for their potential as nerve agents and insecticide antidotes.

Enhancing and Complementary Mechanisms of Synergistic Action of Acori Tatarinowii Rhizoma and Codonopsis Radix for Alzheimer's Disease Based on Systems Pharmacology.

Materials and Methods In this study, a systems pharmacology-based strategy was used to elucidate the synergistic mechanism of Acori Tatarinowii Rhizoma and Codonopsis Radix for the treatment of AD. This novel systems pharmacology model consisted of component information, pharmacokinetic analysis, and pharmacological data. Additionally, the related pathways were compressed using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, and the organ distributions were determined in the BioGPS bank. Results Sixty-eight active ingredients with suitable pharmacokinetic profiles and biological activities were selected through ADME screening in silico. Based on 62 AD-related targets, such as APP, CHRM1, and PTGS1, systematic analysis showed that these two herbs were mainly involved in the PI3K-Akt signaling pathway, MAPK signaling pathway, neuroactive ligand-receptor interaction, and fluid shear stress and atherosclerosis, indicating that they had a synergistic effect on AD. However, ATR acted on the KDR gene, while CR acted on IGF1R, MET, IL1B, and CHUK, showing that they also had complementary effects on AD. The ingredient contribution score involved 29 ingredients contributing 90.14% of the total contribution score of this formula for AD treatment, which emphasized that the effective therapeutic effects of these herbs for AD were derived from both ATR and CR, not a single herb. Organ distribution showed that the targets of the active ingredients were mainly located in the whole blood, the brain, and the muscle, which are associated with AD. Conclusions In sum, our findings suggest that the systems pharmacology methods successfully revealed the synergistic and complementary mechanisms of ATR and CR for the treatment of AD.

Design and Synthesis of CNS-targeted Flavones and Analogues with Neuroprotective Potential Against H2O2- and Aβ1-42-Induced Toxicity in SH-SY5Y Human Neuroblastoma Cells.

With the lack of available drugs able to prevent the progression of Alzheimer’s disease (AD), the discovery of new neuroprotective treatments able to rescue neurons from cell injury is presently a matter of extreme importance and urgency. Here, we were inspired by the widely reported potential of natural flavonoids to build a library of novel flavones, chromen-4-ones and their C-glucosyl derivatives, and to explore their ability as neuroprotective agents with suitable pharmacokinetic profiles. All compounds were firstly evaluated in a parallel artificial membrane permeability assay (PAMPA) to assess their effective permeability across biological membranes, namely the blood-brain barrier (BBB). With this test, we aimed not only at assessing if our candidates would be well-distributed, but also at rationalizing the influence of the sugar moiety on the physicochemical properties. To complement our analysis, logD7.4 was determined. From all screened compounds, the p-morpholinyl flavones stood out for their ability to fully rescue SH-SY5Y human neuroblastoma cells against both H2O2- and Aβ1-42-induced cell death. Cholinesterase inhibition was also evaluated, and modest inhibitory activities were found. This work highlights the potential of C-glucosylflavones as neuroprotective agents, and presents the p-morpholinyl C-glucosylflavone 37, which did not show any cytotoxicity towards HepG2 and Caco-2 cells at 100 μM, as a new lead structure for further development against AD.