RESUMO
In the aftermath of the COVID-19 pandemic, opportunities to modulate biological pathways common to the lifecycles of viruses need to be carefully considered. N-linked glycosylation in humans is mediated exclusively by the oligosaccharyltransferase complex and is frequently hijacked by viruses to facilitate infection. As such, STT3A/B, the catalytic domain of the OST complex, became an intriguing drug target with broad-spectrum antiviral potential. However, due to the critical role N-linked glycosylation plays in a number of fundamental human processes, the toxicological ramifications of STT3A/B inhibition required attention commensurate to that given to antiviral efficacy. Herein, we describe how known STT3A/B inhibitor NGI-1 inspired the discovery of superior tool compounds which were evaluated in in vitro efficacy and translational safety (e.g., CNS, cardiovascular, liver) studies. The described learnings will appeal to those interested in the therapeutic utility of modulating N-linked glycosylation as well as the broader scientific community.
Assuntos
Antivirais , Proteínas de Membrana , SARS-CoV-2 , Sialiltransferases , Antivirais/farmacologia , Antivirais/química , Humanos , Animais , SARS-CoV-2/efeitos dos fármacos , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/metabolismo , Sialiltransferases/antagonistas & inibidores , Sialiltransferases/metabolismo , Descoberta de Drogas , Tratamento Farmacológico da COVID-19 , Glicosilação , Ratos , HexosiltransferasesRESUMO
BACKGROUND: Excessive neutrophil migration has been correlated with influenza symptom severity. Danirixin (GSK1325756), a selective and reversible antagonist of C-X-C chemokine receptor 2, decreases neutrophil activation and transmigration to areas of inflammation. This study evaluated the efficacy and safety of intravenous (IV) danirixin co-administered with oseltamivir for the treatment of adults hospitalized with influenza. METHODS: In this phase 2b, double-blind, 3-arm study (NCT02927431), influenza-positive participants were randomized 2:2:1 to receive danirixin 15mg intravenously (IV) twice daily (bid) + oral oseltamivir 75mg bid (OSV), danirixin 50mg IV bid + OSV, or placebo IV bid + OSV, for up to 5 days. The primary endpoint was time to clinical response (TTCR). RESULTS: In total, 10 participants received study treatment (danirixin 15mg + OSV, n = 4; danirixin 50mg + OSV, n = 4; placebo + OSV, n = 2) before the study was terminated early due to low enrollment. All participants achieved a clinical response. Median (95% confidence interval) TTCR was 4.53 days (2.95, 5.71) for danirixin 15mg + OSV, 4.76 days (2.71, 5.25) for danirixin 50mg + OSV, and 1.33 days (0.71, 1.95) for placebo + OSV. Adverse events (AEs) were generally of mild or moderate intensity; no serious AEs were considered treatment-related. Interleukin-8 levels increased in nasal samples (using synthetic absorptive matrix strips) and decreased serum neutrophil-elastase-mediated degradation of elastin decreased in danirixin-treated participants, suggesting effective target engagement. CONCLUSIONS: Interpretation of efficacy results is restricted by the low participant numbers. The safety and tolerability profile of danirixin was consistent with previous studies. CLINICAL TRIAL INFORMATION: The registration data for the trial are in the ClinicalTrials.gov database, number NCT02927431, and in the EU Clinical Trials Register (https://www.clinicaltrialsregister.eu/) as GSK study 201023, EudraCT 2016-002512-40. Anonymized individual participant data and study documents can be requested for further research from www.clinicalstudydatarequest.com.
RESUMO
BACKGROUND: Danirixin (DNX), a selective and reversible CXC chemokine receptor 2 antagonist, inhibits neutrophil transmigration and activation. This study assessed the safety, tolerability, and clinical effect of DNX with and without oseltamivir (OSV) in adults with acute, uncomplicated influenza. METHODS: This was a placebo-controlled, double-blind, Phase IIa study. Participants (18-64 years) with influenza-like symptoms (onset ≤48 hours) and positive influenza rapid antigen test were randomized 2:1:2:1 to DNX, placebo, DNX+OSV, or OSV (75 mg each, administered twice daily for 5 days) and followed for 28 days. Primary endpoints included frequency of adverse events (AEs) and serious AEs (SAEs). The effect of DNX on virologic response and clinical effect on influenza symptoms were secondary endpoints. RESULTS: A total of 45 participants were enrolled, 35 of whom were confirmed influenza positive by polymerase chain reaction analysis. The highest incidence of AEs was in the placebo group (4 of 7, 57%), followed by the DNX+OSV (7 of 16, 44%), DNX (3 of 15, 20%), and OSV (0 of 7, 0%) groups. One SAE (T-wave abnormality) was reported in the DNX group (unrelated to treatment). No differences in viral load assessments were observed among treatment groups. CONCLUSIONS: Danirixin treatment was well tolerated and did not impede viral clearance.
RESUMO
We previously described the discovery of GSK5852 (1), a non-nucleoside polymerase (NS5B) inhibitor of hepatitis C virus (HCV), in which an N-benzyl boronic acid was essential for potent antiviral activity. Unfortunately, facile benzylic oxidation resulted in a short plasma half-life (5 h) in human volunteers, and a backup program was initiated to remove metabolic liabilities associated with 1. Herein, we describe second-generation NS5B inhibitors including GSK8175 (49), a sulfonamide- N-benzoxaborole analog with low in vivo clearance across preclinical species and broad-spectrum activity against HCV replicons. An X-ray structure of NS5B protein cocrystallized with 49 revealed unique protein-inhibitor interactions mediated by an extensive network of ordered water molecules and the first evidence of boronate complex formation within the binding pocket. In clinical studies, 49 displayed a 60-63 h half-life and a robust decrease in viral RNA levels in HCV-infected patients, thereby validating our hypothesis that reducing benzylic oxidation would improve human pharmacokinetics and lower efficacious doses relative to 1.
Assuntos
Antivirais/farmacologia , Ácidos Borônicos/farmacologia , Desenho de Fármacos , Hepacivirus/efeitos dos fármacos , Inibidores da Síntese de Ácido Nucleico/farmacologia , Animais , Antivirais/química , Antivirais/farmacocinética , Ácidos Borônicos/química , Ácidos Borônicos/farmacocinética , Cristalografia por Raios X , Cães , Meia-Vida , Humanos , Macaca fascicularis , Camundongos , Estrutura Molecular , Inibidores da Síntese de Ácido Nucleico/química , Inibidores da Síntese de Ácido Nucleico/farmacocinética , RatosRESUMO
DNA-encoded library (DEL) technology is a powerful tool commonly used by the pharmaceutical industry for the identification of compounds with affinity to biomolecular targets. Success in this endeavor lies in sampling diverse chemical libraries. However, current DELs tend to be deficient in C(sp3) carbon counts. We report unique solutions to the challenge of increasing both the chemical diversity of these libraries and their C(sp3) carbon counts by merging Ni/photoredox dual catalytic C(sp2)-C(sp3) cross-coupling as well as photoredox-catalyzed radical/polar crossover alkylation protocols with DELs. The successful integration of multiple classes of radical sources enables the rapid incorporation of a diverse set of alkyl fragments.
Assuntos
DNA/química , Níquel/química , Processos Fotoquímicos , Bibliotecas de Moléculas Pequenas , Ar , Alquilação , Catálise , Estrutura Molecular , OxirreduçãoRESUMO
Reporter viruses are useful probes for studying multiple stages of the viral life cycle. Here we describe an expanded toolbox of fluorescent and bioluminescent influenza A reporter viruses. The enhanced utility of these tools enabled kinetic studies of viral attachment, infection, and co-infection. Multi-modal bioluminescence and positron emission tomography-computed tomography (PET/CT) imaging of infected animals revealed that antiviral treatment reduced viral load, dissemination, and inflammation. These new technologies and applications will dramatically accelerate in vitro and in vivo influenza virus studies.
Assuntos
Vírus da Influenza A/crescimento & desenvolvimento , Imagem Multimodal/métodos , Infecções por Orthomyxoviridae/patologia , Infecções por Orthomyxoviridae/virologia , Imagem Corporal Total/métodos , Animais , Antivirais/uso terapêutico , Modelos Animais de Doenças , Feminino , Genes Reporter , Medições Luminescentes/métodos , Camundongos Endogâmicos BALB C , Imagem Óptica/métodos , Infecções por Orthomyxoviridae/tratamento farmacológico , Coloração e Rotulagem/métodos , Resultado do Tratamento , Carga ViralRESUMO
The hepatitis C virus (HCV) NS4B protein is an antiviral therapeutic target for which small-molecule inhibitors have not been shown to exhibit in vivo efficacy. We describe here the in vitro and in vivo antiviral activity of GSK8853, an imidazo[1,2-a]pyrimidine inhibitor that binds NS4B protein. GSK8853 was active against multiple HCV genotypes and developed in vitro resistance mutations in both genotype 1a and genotype 1b replicons localized to the region of NS4B encoding amino acids 94 to 105. A 20-day in vitro treatment of replicons with GSK8853 resulted in a 2-log drop in replicon RNA levels, with no resistance mutation breakthrough. Chimeric replicons containing NS4B sequences matching known virus isolates showed similar responses to a compound with genotype 1a sequences but altered efficacy with genotype 1b sequences, likely corresponding to the presence of known resistance polymorphs in those isolates. In vivo efficacy was tested in a humanized-mouse model of HCV infection, and the results showed a 3-log drop in viral RNA loads over a 7-day period. Analysis of the virus remaining at the end of in vivo treatment revealed resistance mutations encoding amino acid changes that had not been identified by in vitro studies, including NS4B N56I and N99H. Our findings provide an in vivo proof of concept for HCV inhibitors targeting NS4B and demonstrate both the promise and potential pitfalls of developing NS4B inhibitors.
Assuntos
Antivirais/farmacologia , Farmacorresistência Viral/genética , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Imidazóis/farmacologia , Piridinas/farmacologia , RNA Viral/antagonistas & inibidores , Animais , Antivirais/síntese química , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Expressão Gênica , Genótipo , Hepacivirus/genética , Hepacivirus/crescimento & desenvolvimento , Hepatite C/patologia , Hepatite C/virologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/patologia , Hepatócitos/virologia , Humanos , Imidazóis/síntese química , Camundongos , Camundongos Transgênicos , Mutação , Piridinas/síntese química , RNA Viral/biossíntese , RNA Viral/genética , Replicon/efeitos dos fármacos , Resultado do Tratamento , Carga Viral/efeitos dos fármacos , Proteínas não Estruturais Virais , Replicação Viral/efeitos dos fármacosRESUMO
Two novel series of spirocyclic piperidine analogs appended to a pyrazolo[1,5-a]pyridine core were designed, synthesized and evaluated for their anti-HCV activity. A series of piperidine ketals afforded dispiro 6p which showed excellent in vitro anti-HCV activities (EC50 of 1.5nM and 1.2nM against genotype 1a and 1b replicons, respectively). A series of piperidine oxazolidinones afforded 27c which showed EC50's of 10.9nM and 6.1nM against 1a and 1b replicons, respectively. Both compounds 6p and 27c bound directly to non-structural NS4B protein in vitro (IC50's=10.2 and 30.4nM, respectively) and exhibited reduced potency in replicons containing resistance mutations encoding changes in the NS4B protein.
Assuntos
Antivirais/química , Antivirais/farmacologia , Hepacivirus/fisiologia , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/efeitos dos fármacos , Antivirais/síntese química , Desenho de Fármacos , Hepacivirus/efeitos dos fármacos , Hepacivirus/metabolismo , Humanos , Terapia de Alvo Molecular , Compostos de Espiro/síntese químicaRESUMO
We describe the preclinical development and in vivo efficacy of a novel chemical series that inhibits hepatitis C virus replication via direct interaction with the viral nonstructural protein 4B (NS4B). Significant potency improvements were realized through isosteric modifications to our initial lead 1a. The temptation to improve antiviral activity while compromising physicochemical properties was tempered by the judicial use of ligand efficiency indices during lead optimization. In this manner, compound 1a was transformed into (+)-28a which possessed an improved antiviral profile with no increase in molecular weight and only a modest elevation in lipophilicity. Additionally, we employed a chimeric "humanized" mouse model of HCV infection to demonstrate for the first time that a small molecule with high in vitro affinity for NS4B can inhibit viral replication in vivo. This successful proof-of-concept study suggests that drugs targeting NS4B may represent a viable treatment option for curing HCV infection.
Assuntos
Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Proteínas não Estruturais Virais/antagonistas & inibidores , Replicação Viral/efeitos dos fármacos , Animais , Antivirais/química , Antivirais/farmacocinética , Área Sob a Curva , Modelos Animais de Doenças , Hepacivirus/fisiologia , Hepatite C/virologia , Camundongos , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Pró-Fármacos/farmacologiaRESUMO
A boronic acid moiety was found to be a critical pharmacophore for enhanced in vitro potency against wild-type hepatitis C replicons and known clinical polymorphic and resistant HCV mutant replicons. The synthesis, optimization, and structure-activity relationships associated with inhibition of HCV replication in a subgenomic replication system for a series of non-nucleoside boron-containing HCV RNA-dependent RNA polymerase (NS5B) inhibitors are described. A summary of the discovery of 3 (GSK5852), a molecule which entered clinical trials in subjects infected with HCV in 2011, is included.
Assuntos
Antivirais/farmacologia , Ácidos Borônicos/química , Inibidores Enzimáticos/farmacologia , Hepacivirus/efeitos dos fármacos , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Antivirais/química , Descoberta de Drogas , Farmacorresistência Viral/genética , Hepacivirus/enzimologia , Hepacivirus/genética , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/antagonistas & inibidoresRESUMO
A series of imidazo[1,2-a]pyridines which directly bind to HCV Non-Structural Protein 4B (NS4B) is described. This series demonstrates potent in vitro inhibition of HCV replication (EC50 < 10 nM), direct binding to purified NS4B protein (IC50 < 20 nM), and an HCV resistance pattern associated with NS4B (H94N/R, V105L/M, F98L) that are unique among reported HCV clinical assets, suggestive of the potential for additive or synergistic combination with other small molecule inhibitors of HCV replication.
RESUMO
Key binding interactions of the anthranilimide based glycogen phosphorylase a (GPa) inhibitor 2 from X-ray crystallography studies are described. This series of compounds bind to the AMP site of GP. Using the binding information the core and the phenyl urea moieties were optimized. This work culminated in the identification of compounds with single nanomolar potency as well as in vivo efficacy in a diabetic model.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Glicogênio Fosforilase/antagonistas & inibidores , Hipoglicemiantes/síntese química , ortoaminobenzoatos/síntese química , ortoaminobenzoatos/farmacologia , Animais , Glicemia/análise , Técnicas de Química Combinatória , Cristalografia por Raios X , Modelos Animais de Doenças , Hipoglicemiantes/sangue , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Camundongos , Conformação Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Ureia/farmacologia , ortoaminobenzoatos/sangue , ortoaminobenzoatos/químicaRESUMO
Optimization of the amino acid residue within a series of anthranilimide-based glycogen phosphorylase inhibitors is described. These studies culminated in the identification of anthranilimides 16 and 22 which displayed potent in vitro inhibition of GPa in addition to reduced inhibition of CYP2C9 and excellent pharmacokinetic properties.
Assuntos
Hidrocarboneto de Aril Hidroxilases/antagonistas & inibidores , Ácidos Carboxílicos/química , Química Farmacêutica/métodos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glicogênio Fosforilase/antagonistas & inibidores , Imidas/farmacologia , ortoaminobenzoatos/farmacologia , Animais , Hidrocarboneto de Aril Hidroxilases/química , Cristalografia por Raios X , Citocromo P-450 CYP2C9 , Cães , Desenho de Fármacos , Glicina/química , Glicogênio Fosforilase/metabolismo , Humanos , Imidas/química , Concentração Inibidora 50 , Fígado/enzimologia , Conformação Molecular , Ratos , ortoaminobenzoatos/químicaRESUMO
Optimization of the amino acid residue of a series of anthranilimide-based glycogen phosphorylase inhibitors is described leading to the identification of serine and threonine ether analogs. t-Butylthreonine analog 20 displayed potent in vitro inhibition of GPa, low potential for P450 inhibition, and excellent pharmacokinetic properties.
Assuntos
Hidrocarboneto de Aril Hidroxilases/antagonistas & inibidores , Química Farmacêutica/métodos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glicogênio Fosforilase/antagonistas & inibidores , Imidas/química , Serina/química , Treonina/química , ortoaminobenzoatos/química , Animais , Hidrocarboneto de Aril Hidroxilases/química , Cristalografia por Raios X , Citocromo P-450 CYP2C9 , Desenho de Fármacos , Glicina/química , Glicogênio Fosforilase/metabolismo , Humanos , Concentração Inibidora 50 , Fígado/enzimologia , Modelos Químicos , RatosRESUMO
The discovery, synthesis and structure-activity relationship (SAR) of novel carboxylic acid agonists for GPR40 are described. Aryl propionic acid 1, identified from a high throughput screen, was selected for chemical exploration. Compound 2 was identified as our lead molecule through efficient solid phase combinatorial array chemistry and had an attractive in vitro and in vivo pharmacokinetic profile in rat. These ligands may prove useful in establishing a role for GPR40 in insulin regulation.
Assuntos
Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Animais , Disponibilidade Biológica , Células CHO , Ácidos Carboxílicos/farmacocinética , Fenômenos Químicos , Físico-Química , Cricetinae , Cricetulus , Avaliação Pré-Clínica de Medicamentos , Indicadores e Reagentes , Ligantes , Ligação Proteica , Ratos , Relação Estrutura-AtividadeRESUMO
The high expression of MCH in the hypothalamus with the lean hypophagic phenotype coupled with increased resting metabolic rate and resistance to high fat diet-induced obesity of MCH KO mice has spurred considerable efforts to develop small molecule MCHR1 antagonists. Starting from a lead thienopyrimidinone series, structure-activity studies at the 3- and 6-positions of the thienopyrimidinone core afforded potent and selective MCHR1 antagonists with representative examples having suitable pharmacokinetic properties. Based on structure-activity relationships, a structural model for MCHR1 was constructed to explain the binding mode of these antagonists. In general, a good correlation was observed between pKas and activity in the right-hand side of the template, with Asp123 playing an important role in the enhancement of binding affinity. A representative example when evaluated chronically in diet-induced obese mice resulted in good weight loss effects. These antagonists provide a viable lead series in the discovery of new therapies for the treatment of obesity.
Assuntos
Fármacos Antiobesidade/síntese química , Pirimidinas/síntese química , Receptores de Somatostatina/antagonistas & inibidores , Tiofenos/síntese química , Administração Oral , Animais , Fármacos Antiobesidade/química , Fármacos Antiobesidade/farmacologia , Disponibilidade Biológica , Células CHO , Cricetinae , Cricetulus , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , Canais de Potássio Éter-A-Go-Go/fisiologia , Genes Reporter , Meia-Vida , Humanos , Camundongos , Camundongos Obesos , Modelos Moleculares , Pirimidinas/química , Pirimidinas/farmacologia , Ratos , Relação Estrutura-Atividade , Tiofenos/química , Tiofenos/farmacologiaRESUMO
Genetic manipulation studies in mice at both the MCH receptor 1 (MCHR1) as well as the MCH peptide levels have implicated MCHR1 as a key player in energy homeostasis. The phenotype exhibited by these studies, that is, increased metabolic rate, resistance to high fat diet, and subsequent weight loss, has spurred considerable efforts to develop antagonists of MCHR1. In continuation of efforts directed toward this goal, the present work capitalizes on the putative binding mode of an MCH antagonist, resulting in the identification of several novel chemotypes that are potent and selective MCHR1 antagonists. In addition, the favorable pharmacokinetics of representative examples has allowed for the evaluation of an MCHR1 antagonist in a high fat diet-induced obese rodent model of obesity. The tolerability of the right-hand side of the template for diverse chemotypes accompanied by favorable effects on weight loss enhances the attractiveness of this template in the pursuit toward development of effective anti-obesity agents.
Assuntos
Fármacos Antiobesidade/síntese química , Pirimidinas/síntese química , Receptores de Somatostatina/antagonistas & inibidores , Tiofenos/síntese química , Animais , Fármacos Antiobesidade/farmacocinética , Fármacos Antiobesidade/farmacologia , Sítios de Ligação , Células CHO , Cricetinae , Cricetulus , Camundongos , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ratos , Receptores de Somatostatina/química , Relação Estrutura-Atividade , Tiofenos/farmacocinética , Tiofenos/farmacologiaRESUMO
Optimization of a series of constrained melanin-concentrating hormone receptor 1 (MCH R1) antagonists has provided compounds with potent and selective MCH R1 activity. Details of the optimization process are provided and the use of one of the compounds in an animal model of diet-induced obesity is presented.
Assuntos
Pirimidinonas/química , Pirimidinonas/farmacologia , Receptores do Hormônio Hipofisário/antagonistas & inibidores , Animais , Peso Corporal/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos AKR , Modelos Moleculares , Estrutura Molecular , Pirimidinonas/síntese química , Receptores do Hormônio Hipofisário/metabolismo , Relação Estrutura-Atividade , Compostos de Sulfidrila/químicaRESUMO
1. Long chain fatty acids have recently been identified as agonists for the G protein-coupled receptors GPR40 and GPR120. Here, we present the first description of GW9508, a small-molecule agonist of the fatty acid receptors GPR40 and GPR120. In addition, we also describe the pharmacology of GW1100, a selective GPR40 antagonist. These molecules were used to further investigate the role of GPR40 in glucose-stimulated insulin secretion in the MIN6 mouse pancreatic beta-cell line. 2. GW9508 and linoleic acid both stimulated intracellular Ca2+ mobilization in human embryonic kidney (HEK)293 cells expressing GPR40 (pEC50 values of 7.32+/-0.03 and 5.65+/-0.06, respectively) or GPR120 (pEC50 values of 5.46+/-0.09 and 5.89+/-0.04, respectively), but not in the parent HEK-293 cell line. 3. GW1100 dose dependently inhibited GPR40-mediated Ca2+ elevations stimulated by GW9508 and linoleic acid (pIC50 values of 5.99+/-0.03 and 5.99+/-0.06, respectively). GW1100 had no effect on the GPR120-mediated stimulation of intracellular Ca2+ release produced by either GW9508 or linoleic acid. 4. GW9508 dose dependently potentiated glucose-stimulated insulin secretion in MIN6 cells, but not in primary rat or mouse islets. Furthermore, GW9508 was able to potentiate the KCl-mediated increase in insulin secretion in MIN6 cells. The effects of GW9508 on insulin secretion were reversed by GW1100, while linoleic acid-stimulated insulin secretion was partially attenuated by GW1100. 5. These results add further evidence to a link between GPR40 and the ability of fatty acids to acutely potentiate insulin secretion and demonstrate that small-molecule GPR40 agonists are glucose-sensitive insulin secretagogues.
Assuntos
Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Animais , Benzoatos/farmacologia , Células CHO , Linhagem Celular , Células Cultivadas , Cricetinae , Avaliação Pré-Clínica de Medicamentos , Glucose/farmacologia , Humanos , Hipoglicemiantes/farmacologia , Hipolipemiantes/farmacologia , Secreção de Insulina , Metilaminas/farmacologia , Camundongos , Modelos Biológicos , Cloreto de Potássio/farmacologia , Propionatos/farmacologia , Pirimidinas/farmacologia , Spodoptera/citologiaRESUMO
A set of novel heterocyclic pyrimidyl hydrazones has been synthesized as inhibitors of glycogen synthase kinase-3 (GSK-3) with the most active exhibiting low nanomolar activity. Quantum mechanical calculations indicate that of the conformational factors that could determine binding affinity, the planarity of the phenyl ring in relation to the central core and the conformation of the hydrazone chain may be the most influential.