RESUMO
A novel series of quinolinone-based adenosine A(2B) receptor antagonists was identified via high throughput screening of an encoded combinatorial compound collection. Synthesis and assay of a series of analogs highlighted essential structural features of the initial hit. Optimization resulted in an A(2B) antagonist (2i) which exhibited potent activity in a cAMP accumulation assay (5.1 nM) and an IL-8 release assay (0.4 nM).
Assuntos
Antagonistas do Receptor A2 de Adenosina/química , Quinolonas/química , Receptor A2B de Adenosina/química , Antagonistas do Receptor A2 de Adenosina/síntese química , Antagonistas do Receptor A2 de Adenosina/farmacologia , Técnicas de Química Combinatória , Avaliação Pré-Clínica de Medicamentos , Humanos , Microssomos Hepáticos/metabolismo , Quinolonas/síntese química , Quinolonas/farmacologia , Receptor A2B de Adenosina/metabolismo , Relação Estrutura-AtividadeRESUMO
A novel series of adenosine A(2A) receptor antagonists was identified by high-throughput screening of an encoded combinatorial compound collection. The initial hits were optimized for A(2A) binding affinity, A(1) selectivity, and in vitro microsomal stability generating orally available 2-aminoimidazo[4,5-b]pyridine-based A(2A) antagonist leads.
Assuntos
Pirimidinas/farmacologia , Receptor A2A de Adenosina/efeitos dos fármacos , Descoberta de Drogas , Humanos , Ligação de Hidrogênio , Microssomos/efeitos dos fármacos , Receptor A2A de Adenosina/químicaRESUMO
A series of trisubstituted purinones was synthesized and evaluated as A(2A) receptor antagonists. The A(2A) structure-activity relationships at the three substituted positions were studied and selectivity against the A(1) receptor was investigated. One antagonist 12o exhibits a K(i) of 9nM in an A(2A) binding assay, a K(b) of 18nM in an A(2A) cAMP functional assay, and is 220-fold selective over the A(1) receptor.
Assuntos
Antagonistas do Receptor A2 de Adenosina , Purinonas/síntese química , Animais , Humanos , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , Purinonas/metabolismo , Purinonas/farmacologia , Ratos , Receptor A2A de Adenosina/metabolismo , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/metabolismo , Relação Estrutura-AtividadeRESUMO
The discovery and synthesis of a series of 2-amino-5-benzoyl-4-(2-furyl)thiazoles as adenosine A(2A) receptor antagonists from a small-molecule combinatorial library using a high-throughput radioligand-binding assay is described. Antagonists were further characterized in the A(2A) binding assay and an A(1) selectivity assay. Selected examples exhibited excellent affinity for A(2A) and good selectivity versus the A(1) receptor.
Assuntos
Antagonistas de Receptores Purinérgicos P1 , Tiazóis/síntese química , Tiazóis/farmacologia , Alquilação , Linhagem Celular , Técnicas de Química Combinatória , Descoberta de Drogas , Humanos , Ensaio Radioligante , Receptores Purinérgicos P1/metabolismo , Tiazóis/metabolismoRESUMO
At the time of writing, there are seven marketed kinase inhibitor drugs. The first kinase inhibitor, imatinib mesilate (Gleevec, Novartis), came to market in 2001, an inhibitor of the breakpoint cluster region (BCR)/Abelson murine leukemia oncogene homolog (ABL) fusion, platelet-derived growth factor (PDGF) receptor, and c-kit kinases. The most recent kinase inhibitor to come to market, disatinib (Sprycel, Bristol-Myers Squibb), acts on c-SRC, ABL and Bruton's tyrosine kinase. To date, kinase inhibitor drugs are approved for oncology and demonstrate that it is possible to develop compounds with relative selectivity for the target kinase against the broader kinome. However, the use of kinase inhibitors in chronic inflammatory and immunologic diseases may require greater selectivity for the target kinase. This review addresses the opportunities and challenges of kinase inhibition as a therapeutic approach in chronic immune and inflammatory disease.
Assuntos
Doenças do Sistema Imunitário/tratamento farmacológico , Inflamação/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Animais , Benzamidas , Doença Crônica , Ensaios Clínicos como Assunto , Dasatinibe , Humanos , Mesilato de Imatinib , Doenças do Sistema Imunitário/fisiopatologia , Inflamação/fisiopatologia , Piperazinas/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/farmacologia , Tiazóis/farmacologiaRESUMO
A series of 3,4- and 3,5-disubstituted phenyl-containing cyclobutenedione analogues were synthesized and evaluated as CXCR2 receptor antagonists. Variations in the disubstitution pattern of the phenyl ring afforded new compounds with potent CXCR2 binding affinity in the low nanomolar ranges. Moreover, two potent compounds 19 and 26 exhibited good oral pharmacokinetic profiles.
Assuntos
Ciclobutanos/síntese química , Ciclobutanos/farmacologia , Receptores de Interleucina-8B/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Ciclobutanos/química , Haplorrinos , Estrutura Molecular , Ligação Proteica , Ratos , Relação Estrutura-AtividadeRESUMO
Gamma-secretase is a key enzyme involved in the production of beta-amyloid peptides which are believed to play a critical role in the onset and progression of Alzheimer's disease (AD). As such, inhibition of gamma-secretase has been an attractive approach to AD therapy. In this paper, the design, synthesis, and evaluation of tetrahydroquinoline and pyrrolidine sulfonamide carbamates as gamma-secretase inhibitors are described.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Carbamatos/química , Carbamatos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Sulfonamidas/química , Sulfonamidas/farmacologia , Doença de Alzheimer/enzimologia , Carbamatos/síntese química , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Humanos , Pirrolidinas/química , Quinolinas/química , Relação Estrutura-Atividade , Sulfonamidas/síntese químicaRESUMO
The discovery and evaluation of 5-(4-phenylbenzyl)oxazole-4-carboxamides as prostacyclin (IP) receptor antagonists is described. Analogs disclosed showed high affinity for the IP receptor in human platelet membranes with IC50 values of 0.05-0.50 microM, demonstrated functional antagonism by inhibiting cAMP production in HEL cells with IC50 values of 0.016-0.070 microM, and exhibited significant selectivity versus other prostanoid receptors.
Assuntos
Amidas/síntese química , Amidas/farmacologia , Receptores de Prostaglandina/antagonistas & inibidores , Humanos , Concentração Inibidora 50 , Oxazóis/síntese química , Oxazóis/farmacologia , Hidrocarbonetos Policíclicos Aromáticos/síntese química , Hidrocarbonetos Policíclicos Aromáticos/farmacologia , Receptores de Epoprostenol , Relação Estrutura-AtividadeRESUMO
Melanin concentrating hormone (MCH) plays an important role in the regulation of food intake and energy balance in mammals. MCH-1 receptor (MCH1R) deficient mice are lean and resistant to diet-induced obesity. As such, MCH1R antagonists are believed to have potential as possible treatments for obesity. The discovery of a novel class of tetralin ureas as potent MCH1R antagonists is described herein.
Assuntos
Receptores de Somatostatina/antagonistas & inibidores , Tetra-Hidronaftalenos/síntese química , Tetra-Hidronaftalenos/farmacologia , Ureia/análogos & derivados , Ureia/farmacologia , Animais , Ligação Competitiva/efeitos dos fármacos , Células CHO , Cricetinae , Cricetulus , Desenho de Fármacos , Humanos , Camundongos , Camundongos Knockout , Ratos , Receptores de Somatostatina/genética , Relação Estrutura-Atividade , Tetra-Hidronaftalenos/farmacocinética , Distribuição Tecidual , Ureia/farmacocinéticaRESUMO
The melanin-concentrating hormone (MCH) is a hypothalamic peptide that binds to one of two receptors: MCH1 and MCH2. MCH1 is well-recognized for its orexigenic properties but may control a number of other physiological activities from both the CNS and the periphery. MCH2 is not expressed in rodents and so its physiological functions in humans are not well understood. This review highlights the discovery and development of multiple structural classes of MCH1 small-molecule antagonists that show impressive levels of efficacy in rodent models of obesity. In some cases these compounds show improved and more sustained efficacy compared to clinically-approved antiobesity pharmaceutical agents. Despite such compelling efficacy, a number of chemical series are unable to progress to the clinic due to selectivity issues. Ongoing efforts to circumvent these challenges are addressed.
RESUMO
Structure-activity studies on lead cyclobutenedione 3 led to the discovery of 4 (SCH 527123), a potent, orally bioavailable CXCR2/CXCR1 receptor antagonist with excellent cell-based activity. Compound 4 displayed good oral bioavailability in rat and may be a potential therapeutic agent for the treatment of various inflammatory diseases.
Assuntos
Benzamidas/farmacologia , Ciclobutanos/farmacologia , Receptores de Interleucina-8A/antagonistas & inibidores , Receptores de Interleucina-8B/antagonistas & inibidores , Administração Oral , Animais , Benzamidas/administração & dosagem , Benzamidas/síntese química , Disponibilidade Biológica , Ciclobutanos/administração & dosagem , Ciclobutanos/síntese química , Estrutura Molecular , Ratos , Receptores de Interleucina-8A/metabolismo , Receptores de Interleucina-8B/metabolismo , Relação Estrutura-AtividadeRESUMO
Since its discovery as the first receptor for the orexigenic neuropeptide melanin-concentrating hormone (MCH), the MCH receptor, MCHR1, has been actively pursued for therapeutic intervention in the treatment of obesity. Mice with targeted deletion of MCHR1 or its cognate ligand, MCH, generally have decreased body weight and fat mass and are resistant to diet-induced obesity compared with their wild-type counterparts. Mice treated via intracerebroventricular infusion with MCH, or that overexpress MCH or MCHR1, exhibit weight gain compared with control animals. MCHR1 is also a central target of leptin signaling and appears to be a mediator of insulin resistance. The distribution of MCH and MCHR1 in rat brain, outside of regions that control appetite and satiety, has led to the finding that MCH signaling participates in other functions such as emotion and stress. This review will describe in detail the biological studies that show how MCH and MCHR1 control numerous physiological functions. The current status of the development of MCHR1 antagonists for clinical use will also be assessed. Given the substantial link between obesity and its many associated afflictions, a single pharmaceutical agent that could be used to treat multiple pathologies would be welcome.
RESUMO
Since its discovery as the first receptor for the orexigenic neuropeptide melanin-concentrating hormone (MCH), the MCH receptor, MCHR1, has been actively pursued for therapeutic intervention in the treatment of obesity. Mice with targeted deletion of MCHR1 or its cognate ligand, MCH, generally have decreased body weight and fat mass and are resistant to diet-induced obesity compared with their wild-type counterparts. Mice treated via intracerebroventricular infusion with MCH, or that overexpress MCH or MCHR1, exhibit weight gain compared with control animals. MCHR1 is also a central target of leptin signaling and appears to be a mediator of insulin resistance. The distribution of MCH and MCHR1 in rat brain, outside of regions that control appetite and satiety, has led to the finding that MCH signaling participates in other functions such as emotion and stress. This review will describe in detail the biological studies that show how MCH and MCHR1 control numerous physiological functions. The current status of the development of MCHR1 antagonists for clinical use will also be assessed. Given the substantial link between obesity and its many associated afflictions, a single pharmaceutical agent that could be used to treat multiple pathologies would be welcome.
Assuntos
Hormônios Hipotalâmicos/fisiologia , Hipotálamo/fisiologia , Melaninas/fisiologia , Hormônios Hipofisários/fisiologia , Receptores de Somatostatina/fisiologia , Sequência de Aminoácidos , Animais , Peso Corporal/efeitos dos fármacos , Peso Corporal/fisiologia , Humanos , Hormônios Hipotalâmicos/antagonistas & inibidores , Hormônios Hipotalâmicos/genética , Hipotálamo/efeitos dos fármacos , Melaninas/antagonistas & inibidores , Melaninas/genética , Dados de Sequência Molecular , Obesidade/fisiopatologia , Obesidade/prevenção & controle , Hormônios Hipofisários/antagonistas & inibidores , Hormônios Hipofisários/genética , Receptores de Somatostatina/antagonistas & inibidores , Receptores de Somatostatina/genética , Homologia de Sequência de AminoácidosRESUMO
The development of structure-activity relationships (SARs) relating to the function of a biological protein is often a long and protracted undertaking when using an iterative medicinal chemistry approach. High throughput screening of ECLiPS (Encoded Combinatorial Libraries on Polymeric Support) libraries can be used to simplify this process. In this paper, we illustrate how a large ECLiPS library of 26,908 compounds, based on a tricyclic core structure, was used to define a multitude of SARs for the oncogenic target, farnesyltransferase (FTase). This library, FT-2, was prepared using a split-and-pool approach in which small molecules are constructed on resin that contains tag/linker constructs to track the synthetic process [1-5] Highly defined SARs were produced from this screen that enhanced our understanding of FTase binding site interactions. The pivotal compounds culled from this library were potent in both cell-free and cell-based FTase assays, selective over the closely related enzyme, geranylgeranyltransferase I (GGTase I), and inhibited the adherent-independent growth of a transformed cell line.
Assuntos
Técnicas de Química Combinatória , Inibidores Enzimáticos/farmacologia , Farnesiltranstransferase/antagonistas & inibidores , Alquil e Aril Transferases/antagonistas & inibidores , Sítios de Ligação , Bioensaio , Técnicas de Cultura de Células , Linhagem Celular Transformada/efeitos dos fármacos , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais Cultivadas/efeitos dos fármacosRESUMO
A novel series of 3,4-diaminocyclobut-3-ene-1,2-diones was prepared and found to show potent inhibitory activity of CXCR2 binding and IL-8-mediated chemotaxis of a CXCR2-expressing cell line. Microsome stability and Caco2 studies were subsequently used to show that compounds of this chemotype are predicted to have good oral bioavailability and are thus suitable for pharmaceutical development.
Assuntos
Ciclobutanos/síntese química , Ciclobutanos/farmacologia , Receptores de Interleucina-8B/antagonistas & inibidores , Administração Oral , Disponibilidade Biológica , Células CACO-2 , Ciclobutanos/química , Ciclobutanos/farmacocinética , Humanos , Microssomos Hepáticos/metabolismo , Relação Estrutura-AtividadeRESUMO
Farnesyltransferase inhibitors identified from an ECLiPS library were optimized using solution-phase synthesis. X-ray crystallography of inhibited complexes was used to identify substructures that coordinate to the active site zinc. The X-ray structures were ultimately used to guide the design of second-generation analogs with FTase IC(50)s of less than 1.0 nM.
Assuntos
Inibidores Enzimáticos/farmacologia , Farnesiltranstransferase/antagonistas & inibidores , Biblioteca de Peptídeos , Zinco/química , Animais , Sítios de Ligação , Catálise , Cristalografia por Raios X , Inibidores Enzimáticos/síntese química , Farnesiltranstransferase/síntese química , Concentração Inibidora 50 , Camundongos , Células NIH 3T3 , Relação Estrutura-AtividadeRESUMO
In order to fully explore structure-activity relationships at the 1- and 2-positions of the piperazine core of tricyclic farnesyltransferase inhibitors, an 11,718-member ECLiPS library was synthesized and screened in a farnesyltransferase scintillation proximity assay. A detailed description of the library and analyses of the screening data will be provided.
Assuntos
Inibidores Enzimáticos/química , Farnesiltranstransferase/antagonistas & inibidores , Piperazinas/química , Piperazinas/farmacologia , Inibidores Enzimáticos/farmacologia , Imidazóis/química , Imidazóis/farmacologia , Cinética , Relação Estrutura-AtividadeRESUMO
An encoded combinatorial library based on aryl and biaryl piperidine scaffolds was designed and synthesized. Screening of this library resulted in the discovery of high-nanomolar biaryl piperidine-based MCH1 receptor antagonists. Follow-up optimization using a parallel synthesis provided potent, single digit nanomolar antagonists.
Assuntos
Piperidinas/síntese química , Piperidinas/farmacologia , Receptores de Somatostatina/antagonistas & inibidores , Técnicas de Química Combinatória , Desenho de Fármacos , Humanos , Estrutura Molecular , Piperidinas/química , Relação Estrutura-AtividadeRESUMO
-4-Amino-2-arylbutylbenzamides such as 1 were identified as micromolar MCH 1 receptor (MCH1R) antagonists via screening using a scintillation proximity assay based on [125I]-MCH binding to recombinant, human MCH1R. Subsequent lead optimization efforts using solid-phase parallel synthesis resulted in the defined structure-activity relationships and the identification of 4-amino-2-biarylbutylureas, such as 11g, as potent single digit nanomolar MCH1R antagonists.