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1.
Bioorg Med Chem Lett ; 30(22): 127531, 2020 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-32890685

RESUMO

Previous studies have identified a series of imidazo[1,2-a]pyridine (IZP) derivatives as potent allosteric inhibitors of HIV-1 integrase (ALLINIs) and virus infection in cell culture. However, IZPs were also found to be relatively potent activators of the pregnane-X receptor (PXR), raising the specter of induction of CYP-mediated drug disposition pathways. In an attempt to modify PXR activity without affecting anti-HIV-1 activity, rational structure-based design and modeling approaches were used. An X-ray cocrystal structure of (S,S)-1 in the PXR ligand binding domain (LBD) allowed an examination of the potential of rational structural modifications designed to abrogate PXR. The introduction of bulky basic amines at the C-8 position provided macrocyclic IZP derivatives that displayed potent HIV-1 inhibitory activity in cell culture with no detectable PXR transactivation at the highest concentration tested.


Assuntos
Fármacos Anti-HIV/farmacologia , Inibidores de Integrase de HIV/farmacologia , HIV-1/efeitos dos fármacos , Compostos Macrocíclicos/farmacologia , Receptor de Pregnano X/antagonistas & inibidores , Regulação Alostérica/efeitos dos fármacos , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Células Cultivadas , Relação Dose-Resposta a Droga , Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/química , Humanos , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Receptor de Pregnano X/metabolismo , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacos
2.
J Pharmacol Exp Ther ; 356(2): 293-304, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26582730

RESUMO

The muscarinic acetylcholine receptor subtype 1 (M1) receptors play an important role in cognition and memory, and are considered to be attractive targets for the development of novel medications to treat cognitive impairments seen in schizophrenia and Alzheimer's disease. Indeed, the M1 agonist xanomeline has been shown to produce beneficial cognitive effects in both Alzheimer's disease and schizophrenia patients. Unfortunately, the therapeutic utility of xanomeline was limited by cholinergic side effects (sweating, salivation, gastrointestinal distress), which are believed to result from nonselective activation of other muscarinic receptor subtypes such as M2 and M3. Therefore, drug discovery efforts targeting the M1 receptor have focused on the discovery of compounds with improved selectivity profiles. Recently, allosteric M1 receptor ligands have been described, which exhibit excellent selectivity for M1 over other muscarinic receptor subtypes. In the current study, the following three compounds with mixed agonist/positive allosteric modulator activities that are highly functionally selective for the M1 receptor were tested in rats, dogs, and cynomologous monkeys: (3-((1S,2S)-2-hydrocyclohexyl)-6-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)benzo[h]quinazolin-4(3H)-one; 1-((4-cyano-4-(pyridin-2-yl)piperidin-1-yl)methyl)-4-oxo-4H-quinolizine-3-carboxylic acid; and (R)-ethyl 3-(2-methylbenzamido)-[1,4'-bipiperidine]-1'-carboxylate). Despite their selectivity for the M1 receptor, all three compounds elicited cholinergic side effects such as salivation, diarrhea, and emesis. These effects could not be explained by activity at other muscarinic receptor subtypes, or by activity at other receptors tested. Together, these results suggest that activation of M1 receptors alone is sufficient to produce unwanted cholinergic side effects such as those seen with xanomeline. This has important implications for the development of M1 receptor-targeted therapeutics since it suggests that dose-limiting cholinergic side effects still reside in M1 receptor selective activators.


Assuntos
Agonistas Muscarínicos/metabolismo , Agonistas Muscarínicos/farmacologia , Receptor Muscarínico M1/agonistas , Receptor Muscarínico M1/metabolismo , Animais , Células CHO , Cricetinae , Cricetulus , Cães , Relação Dose-Resposta a Droga , Humanos , Macaca fascicularis , Masculino , Camundongos , Ratos , Ratos Sprague-Dawley
3.
Proc Natl Acad Sci U S A ; 108(37): 15366-71, 2011 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-21896751

RESUMO

Influenza nucleoprotein (NP) plays multiple roles in the virus life cycle, including an essential function in viral replication as an integral component of the ribonucleoprotein complex, associating with viral RNA and polymerase within the viral core. The multifunctional nature of NP makes it an attractive target for antiviral intervention, and inhibitors targeting this protein have recently been reported. In a parallel effort, we discovered a structurally similar series of influenza replication inhibitors and show that they interfere with NP-dependent processes via formation of higher-order NP oligomers. Support for this unique mechanism is provided by site-directed mutagenesis studies, biophysical characterization of the oligomeric ligand:NP complex, and an X-ray cocrystal structure of an NP dimer of trimers (or hexamer) comprising three NP_A:NP_B dimeric subunits. Each NP_A:NP_B dimeric subunit contains two ligands that bridge two composite, protein-spanning binding sites in an antiparallel orientation to form a stable quaternary complex. Optimization of the initial screening hit produced an analog that protects mice from influenza-induced weight loss and mortality by reducing viral titers to undetectable levels throughout the course of treatment.


Assuntos
Antivirais/farmacologia , Nucleoproteínas/química , Nucleoproteínas/metabolismo , Orthomyxoviridae/fisiologia , Bibliotecas de Moléculas Pequenas/farmacologia , Replicação Viral/efeitos dos fármacos , Animais , Antivirais/uso terapêutico , Cristalografia por Raios X , Modelos Animais de Doenças , Ensaios de Triagem em Larga Escala , Hidrodinâmica , Camundongos , Modelos Moleculares , Nucleoproteínas/ultraestrutura , Orthomyxoviridae/efeitos dos fármacos , Infecções por Orthomyxoviridae/tratamento farmacológico , Infecções por Orthomyxoviridae/virologia , Multimerização Proteica/efeitos dos fármacos , Estrutura Quaternária de Proteína , Bibliotecas de Moléculas Pequenas/uso terapêutico , Soluções
4.
PLoS Pathog ; 6(9): e1001086, 2010 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-20838466

RESUMO

Small molecule inhibitors of hepatitis C virus (HCV) are being developed to complement or replace treatments with pegylated interferons and ribavirin, which have poor response rates and significant side effects. Resistance to these inhibitors emerges rapidly in the clinic, suggesting that successful therapy will involve combination therapy with multiple inhibitors of different targets. The entry process of HCV into hepatocytes represents another series of potential targets for therapeutic intervention, involving viral structural proteins that have not been extensively explored due to experimental limitations. To discover HCV entry inhibitors, we utilized HCV pseudoparticles (HCVpp) incorporating E1-E2 envelope proteins from a genotype 1b clinical isolate. Screening of a small molecule library identified a potent HCV-specific triazine inhibitor, EI-1. A series of HCVpp with E1-E2 sequences from various HCV isolates was used to show activity against all genotype 1a and 1b HCVpp tested, with median EC50 values of 0.134 and 0.027 µM, respectively. Time-of-addition experiments demonstrated a block in HCVpp entry, downstream of initial attachment to the cell surface, and prior to or concomitant with bafilomycin inhibition of endosomal acidification. EI-1 was equally active against cell-culture adapted HCV (HCVcc), blocking both cell-free entry and cell-to-cell transmission of virus. HCVcc with high-level resistance to EI-1 was selected by sequential passage in the presence of inhibitor, and resistance was shown to be conferred by changes to residue 719 in the carboxy-terminal transmembrane anchor region of E2, implicating this envelope protein in EI-1 susceptibility. Combinations of EI-1 with interferon, or inhibitors of NS3 or NS5A, resulted in additive to synergistic activity. These results suggest that inhibitors of HCV entry could be added to replication inhibitors and interferons already in development.


Assuntos
Antivirais/uso terapêutico , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Hepatócitos/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/metabolismo , Internalização do Vírus/efeitos dos fármacos , Sequência de Aminoácidos , Antígenos CD/genética , Antígenos CD/metabolismo , Antivirais/isolamento & purificação , Células Cultivadas , Farmacorresistência Viral , Sinergismo Farmacológico , Hepacivirus/isolamento & purificação , Hepacivirus/metabolismo , Hepatite C/genética , Hepatite C/virologia , Hepatócitos/citologia , Hepatócitos/metabolismo , Humanos , Interferons/uso terapêutico , Dados de Sequência Molecular , Homologia de Sequência de Aminoácidos , Bibliotecas de Moléculas Pequenas/análise , Tetraspanina 28 , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/metabolismo
5.
J Comb Chem ; 12(1): 84-90, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-19902958

RESUMO

A novel series of HIV-1 integrase inhibitors were identified from a 100 member (4R(1) x 5R(2) x 5R(3)) library of pyrrolidinedione amides. A solid-phase route was developed which facilitates the simultaneous variation at R(1), R(2), and R(3) of the pyrrolidinedione scaffold. The resulting library samples were assayed for HIV-1 integrase activity and analyzed to determine the R(1), R(2), and R(3) reagent contributions towards the activity.


Assuntos
Desenho de Fármacos , Inibidores de Integrase de HIV/síntese química , HIV-1/efeitos dos fármacos , Succinimidas/síntese química , Técnicas de Química Combinatória/métodos , Inibidores de Integrase de HIV/farmacologia , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Succinimidas/química , Succinimidas/farmacologia
6.
J Med Chem ; 63(5): 2620-2637, 2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-32081010

RESUMO

The standard of care for HIV-1 infection, highly active antiretroviral therapy (HAART), combines two or more drugs from at least two classes. Even with the success of HAART, new drugs with novel mechanisms are needed to combat viral resistance, improve adherence, and mitigate toxicities. Active site inhibitors of HIV-1 integrase are clinically validated for the treatment of HIV-1 infection. Here we describe allosteric inhibitors of HIV-1 integrase that bind to the LEDGF/p75 interaction site and disrupt the structure of the integrase multimer that is required for the HIV-1 maturation. A series of pyrazolopyrimidine-based inhibitors was developed with a vector in the 2-position that was optimized by structure-guided compound design. This resulted in the discovery of pyrazolopyrimidine 3, which was optimized at the 2- and 7-positions to afford 26 and 29 as potent allosteric inhibitors of HIV-1 integrase that exhibited low nanomolar antiviral potency in cell culture and encouraging PK properties.


Assuntos
Regulação Alostérica/efeitos dos fármacos , Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/farmacologia , HIV-1/efeitos dos fármacos , Pirazóis/química , Pirazóis/farmacologia , Piridinas/química , Piridinas/farmacologia , Administração Oral , Animais , Descoberta de Drogas , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Integrase de HIV/metabolismo , Inibidores de Integrase de HIV/administração & dosagem , Inibidores de Integrase de HIV/farmacocinética , Humanos , Masculino , Simulação de Acoplamento Molecular , Pirazóis/administração & dosagem , Pirazóis/farmacocinética , Piridinas/administração & dosagem , Piridinas/farmacocinética , Ratos Sprague-Dawley
7.
Neuropharmacology ; 102: 121-35, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26522433

RESUMO

Phosphodiesterase 10A (PDE10A) inhibitors increase the functionality of striatal medium spiny neurons and produce antipsychotic-like effects in rodents by blocking PDE10A mediated hydrolysis of cAMP and/or cGMP. In the current study, we characterized a radiolabeled PDE10A inhibitor, [(3)H]BMS-843496, and developed an ex vivo PDE10 binding autoradiographic assay to explore the relationship between PDE10 binding site occupancy and the observed biochemical and behavioral effects of PDE10 inhibitors in mice. [(3)H]BMS-843496 is a potent PDE10A inhibitor with a binding affinity (KD) of 0.15 nM and a functional selectivity of >100-fold over other PDE subtypes tested. Specific [(3)H]BMS-843496 binding sites were dominant in the basal ganglia, especially the striatum, with low to moderate binding in the cortical and hippocampal areas, of the mouse and monkey brain. Systemic administration of PDE10 inhibitors produced a dose- and plasma/brain concentration-dependent increase in PDE10A occupancy measured in the striatum. PDE10A occupancy was positively correlated with striatal pCREB expression levels. PDE10A occupancy was also correlated with antipsychotic-like effects measured using the conditioned avoidance response model; a minimum of ∼40% occupancy was typically required to achieve efficacy. In contrast, a clear relationship between PDE10A occupancy and catalepsy scores, a potential extrapyramidal symptom readout in rodent, was not evident.


Assuntos
Antipsicóticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Inibidores de Fosfodiesterase/farmacologia , Animais , Sítios de Ligação , Encéfalo/metabolismo , Relação Dose-Resposta a Droga , Macaca fascicularis , Masculino , Camundongos , Camundongos Knockout , Diester Fosfórico Hidrolases/genética , Diester Fosfórico Hidrolases/metabolismo
8.
ACS Comb Sci ; 14(3): 197-204, 2012 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-22340081

RESUMO

We have developed a solid phase synthesis route to 1,5-substituted pyrazole-4-carboxamides with three diversity points aimed at the discovery of new compounds as potential G-Protein coupled receptor (GPCR) ligands. The new chemistry involves acylation of a resin bound secondary amine with a ß-ketoester via transamidation, conversion of the resulting ß-ketoamide to the corresponding vinylogous amide, pyrazole formation upon reaction with a aryl hydrzine, and cleavage of the product from the resin. Using the reported methodology, we describe the syntheses of multiple arrays of pyrazoles that were used collectively to construct a library of more than 1000 analogues. Several members of this library displayed submicromolar antagonist activities at the cannabinoid subtype 1 (CB-1) receptor.


Assuntos
Amidas/química , Descoberta de Drogas , Pirazóis/química , Receptor CB1 de Canabinoide/antagonistas & inibidores , Amidas/farmacologia , Concentração Inibidora 50 , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , Pirazóis/farmacologia , Receptor CB1 de Canabinoide/química , Técnicas de Síntese em Fase Sólida
9.
Expert Opin Ther Pat ; 21(8): 1173-89, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21599420

RESUMO

INTRODUCTION: The use of inhibitors of HIV-1 integrase for treating HIV-1 infection has proven to be very beneficial. Raltegravir, a strand transfer inhibitor, has been approved for use both as a first-line therapy and in treatment-experienced patients. A second compound in this class, elvitegravir, is in Phase III clinical trials and is being developed as part of a once daily fixed dose combination pill. With widespread use of raltegravir, viral resistance has emerged with surprising facility. Attempts to use raltegravir on a once daily dosing regimen have been unsuccessful whilst elvitegravir cannot be delivered daily without the aid of a pharmacokinetic (PK)-enhancing agent. Thus, there is a need for second generation compounds to address these issues. AREAS COVERED: Patent applications claiming compounds useful as inhibitors of HIV-1 integrase are reviewed in this paper, along with compounds related to the strand transfer inhibitors. EXPERT OPINION: The field appears to be more focused on developing compounds which address the issues identified for the first generation compounds, raltegravir and elvitegravir. Patent activity around new strand transfer inhibitors claims compounds active against first generation resistant mutations and having PK profiles suitable for daily dosing. Advancements in this area have been rapid and several compounds described in these patent applications are currently in clinical trials. Bolstered by recent mechanistic discoveries, compounds inhibiting processes other than strand transfer have begun to emerge. It is foreseeable that a second generation integrase inhibitor could be approved for treatment in the coming years.


Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/uso terapêutico , Integrase de HIV/metabolismo , HIV-1/efeitos dos fármacos , Animais , Farmacorresistência Viral , Infecções por HIV/virologia , Inibidores de Integrase de HIV/administração & dosagem , Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/farmacocinética , HIV-1/enzimologia , Humanos , Patentes como Assunto , Relação Estrutura-Atividade
10.
Eur J Pharmacol ; 651(1-3): 9-17, 2011 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-21044623

RESUMO

The cannabinoid CB(1) G protein-coupled receptor has been shown to be a regulator of food consumption and has been studied extensively as a drug target for the treatment of obesity. To advance understanding of the receptor's three-dimensional structure, we performed mutagenesis studies at human cannabinoid CB(1) receptor residues F200 and S383 and measured changes in activity and binding affinity of compounds from two recently discovered active chemotypes, arylsulfonamide agonists and tetrahydroquinoline-based inverse agonists, as well as literature compounds. Our results add support to previous findings that both agonists and inverse agonists show varied patterns of binding at the two mutated residue sites, suggesting multiple subsites for binding to the cannabinoid CB(1) receptor for both functional types of ligands. We additionally find that an F200L mutation in the receptor largely restores binding affinity to ligands and significantly decreases constitutive activity when compared to F200A, resulting in a receptor phenotype that is closer to the wild-type receptor. The results downplay the importance of aromatic stacking interactions at F200 and suggest that a bulky hydrophobic contact is largely sufficient to provide significant receptor function and binding affinity to cannabinoid CB(1) receptor ligands.


Assuntos
Mutagênese , Fenilalanina , Receptor CB1 de Canabinoide/química , Receptor CB1 de Canabinoide/metabolismo , Serina , Animais , Benzoatos/metabolismo , Benzoatos/farmacologia , Células CHO , Cricetinae , Cricetulus , Agonismo Inverso de Drogas , Humanos , Interações Hidrofóbicas e Hidrofílicas , Ligantes , Fenilalanina/genética , Fenilalanina/metabolismo , Ligação Proteica , Proteínas Proto-Oncogênicas c-myc/metabolismo , Quinolinas/metabolismo , Quinolinas/farmacologia , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/genética , Serina/genética , Serina/metabolismo , Sulfonamidas/metabolismo , Sulfonamidas/farmacologia
12.
Bioorg Med Chem Lett ; 17(14): 3978-82, 2007 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-17513109

RESUMO

Structure-activity relationships for a series of pyrazine carboxamide CB1 antagonists are reported. Pharmaceutical properties of the series are improved via inclusion of hydroxyl-containing sidechains. This structural modification sufficiently improved ADME properties of an orally inactive series such that food intake reduction was achieved in rat feeding models. Compound 35 elicits a 46% reduction in food intake in ad libidum fed rats 4-h post-dose.


Assuntos
Amidas/farmacologia , Pirazinamida/análogos & derivados , Receptor CB1 de Canabinoide/antagonistas & inibidores , Amidas/química , Animais , Pirazinamida/química , Pirazinamida/farmacologia , Ratos , Relação Estrutura-Atividade
13.
Bioorg Med Chem Lett ; 16(22): 5818-21, 2006 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-16971121

RESUMO

Integrase is one of three enzymes expressed by HIV and represents a validated target for therapy. A previous study of the diketoacid-based chemotype suggested that there are two aryl-binding domains on integrase. In this study, modifications to the indole-based diketoacid chemotype are explored. It is demonstrated that the indole group can be replaced with secondary but not tertiary (e.g., N-methyl) aniline-based amides without sacrificing in vitro inhibitory activity. The difference in activity between the secondary and tertiary amides is most likely due to the opposite conformational preferences of the amide bonds, s-trans for the secondary-amide and s-cis for the tertiary-amide. However, it was found that the conformational preference of the tertiary amide can be reversed by incorporating the amide nitrogen atom into an indoline heterocycle, resulting in very potent integrase inhibitors.


Assuntos
Anilidas/síntese química , Anilidas/farmacologia , Inibidores de Integrase de HIV/farmacologia , HIV-1/efeitos dos fármacos , Cetoácidos/síntese química , Cetoácidos/farmacologia , Amidas/química , Sítios de Ligação , Cátions , Desenho de Fármacos , Humanos , Magnésio/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade
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