Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 13 de 13
Filtrar
1.
Bioorg Med Chem Lett ; 95: 129487, 2023 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-37734423

RESUMO

The G2019S variant of LRRK2, which causes an increase in kinase activity, is associated with the occurrence of Parkinson's disease (PD). Potent, mutation-selective, and brain penetrant inhibitors of LRRK2 can suppress the biological effects specific to G2019S-LRRK2 that cause pathogenicity. We report the discovery of a series of cyanoindane and cyanotetralin kinase inhibitors culminating in compound 34 that demonstrated selective inhibition of phosphorylation of LRRK2 in the mouse brain. These novel inhibitors may further enable the precision medicine path for future PD therapeutics.

2.
Bioorg Med Chem Lett ; 20(23): 7120-3, 2010 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-20951033

RESUMO

A novel class of benzimidazole NPY Y5 receptor antagonists was prepared exploiting a privileged spirocarbamate moiety. The structure-activity relationship of this series and efforts to achieve a profile suitable for further development and an appropriate pharmacokinetic profile in rat are described. Optimisation led to the identification of the brain penetrant, orally bioavailable Y5 antagonist 9b which significantly inhibited the food intake induced by a Y5 selective agonist with a minimal effective dose of 30mg/kg po.


Assuntos
Benzimidazóis/química , Benzimidazóis/farmacologia , Desenho de Fármacos , Ingestão de Alimentos/efeitos dos fármacos , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Administração Oral , Animais , Benzimidazóis/síntese química , Benzimidazóis/farmacocinética , Encéfalo/metabolismo , Relação Dose-Resposta a Droga , Ratos , Relação Estrutura-Atividade
3.
J Med Chem ; 63(23): 14821-14839, 2020 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-33197196

RESUMO

Pathogenic variants in the leucine-rich repeat kinase 2 (LRRK2) gene have been identified that increase the risk for developing Parkinson's disease in a dominantly inherited fashion. These pathogenic variants, of which G2019S is the most common, cause abnormally high kinase activity, and compounds that inhibit this activity are being pursued as potentially disease-modifying therapeutics. Because LRRK2 regulates important cellular processes, developing inhibitors that can selectively target the pathogenic variant while sparing normal LRRK2 activity could offer potential advantages in heterozygous carriers. We conducted a high-throughput screen and identified a single selective compound that preferentially inhibited G2019S-LRRK2. Optimization of this scaffold led to a series of novel, potent, and highly selective G2019S-LRRK2 inhibitors.


Assuntos
Indazóis/farmacologia , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Tetrazóis/farmacologia , Animais , Células HEK293 , Ensaios de Triagem em Larga Escala , Humanos , Indazóis/síntese química , Indazóis/farmacocinética , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Camundongos , Estrutura Molecular , Mutação , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/síntese química , Pirimidinas/farmacocinética , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/farmacocinética , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-Atividade , Tetrazóis/síntese química , Tetrazóis/farmacocinética
4.
Farmaco ; 58(10): 1005-9, 2003 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-14505730

RESUMO

Following the disclosure of 3-(1,2,2-trimethylpropyl) 4-[3,5-dimethyl-2-propyloxycarbonyl]pyrrolecarboxylate as a potent and selective mGluR1 non-competitive antagonist, the role and the importance of the pyrrole template were investigated. Different aromatic moieties were investigated as possible bio-isosteric replacement of the original scaffold and some of them were shown to be partially able to mimic the properties of the original pyrrole ring.


Assuntos
Analgésicos não Narcóticos/síntese química , Pirróis/síntese química , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Analgésicos não Narcóticos/farmacologia , Animais , Derivados de Benzeno/química , Derivados de Benzeno/farmacologia , Ligação Competitiva/efeitos dos fármacos , Células CHO , Cricetinae , Ésteres/síntese química , Ésteres/farmacologia , Concentração Inibidora 50 , Camundongos , Nociceptores/efeitos dos fármacos , Medição da Dor , Pirróis/farmacologia , Ratos , Receptores de Glutamato Metabotrópico/química , Receptores de Glutamato Metabotrópico/genética , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Relação Estrutura-Atividade , Tiofenos/química , Tiofenos/farmacologia
5.
Farmaco ; 59(3): 175-83, 2004 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-14987980

RESUMO

Following the recent disclosure of 3-methyl pyrrole-2,4-dicarboxylic acid 2-propyl ester 4-(1,2,2-trimethyl-propyl) ester, a potent and selective mGluR1 non-competitive antagonist, we report here a detailed exploration of the C-2 position of this scaffold with the preparation of differently substituted amides. Great improvement of the pharmacokinetic properties has been achieved through this exercise.


Assuntos
Ésteres/síntese química , Ésteres/farmacologia , Pirróis/síntese química , Pirróis/farmacologia , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Amidas/síntese química , Amidas/farmacocinética , Animais , Azidas/síntese química , Azidas/farmacocinética , Fenômenos Químicos , Físico-Química , Cromatografia Líquida de Alta Pressão , Cromatografia em Camada Fina , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/farmacocinética , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Camundongos , Conformação Molecular , Ratos , Solubilidade , Espectrofotometria Infravermelho , Relação Estrutura-Atividade
6.
Eur J Pharmacol ; 650(1): 178-83, 2011 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-21034740

RESUMO

A novel growth hormone secretagogues type 1a (GHS1a) receptors antagonist (2R)-N'-[3,5- bis(trifluoromethyl)phenyl]-2-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2-(3- pyridinyl)ethanohydrazide (GSK1614343) was functionally characterised in rat pituitary adenoma cell line, RC-4B/C endogenously expressing GHS1a receptors. The antagonism profile of GSK1614343 was compared with that of 6-[(4-fluorophenyl)oxy]-2-methyl-3-{[(3S)-1-(1-methylethyl)-3- piperidinyl]methyl}-4(3H)-quinazolinone (YIL-781) another ghrelin receptor antagonist recently published. The activity of both compounds was also evaluated at rat recombinant GHS1a receptors. The characterization of the two antagonists was performed by intracellular calcium mobilization measurements by using fluorometric imaging plate reader (FLIPR) technology and inositol phosphate (IP) turnover measurements by [3H]-IP accumulation assay. RC-4B/C and U2-OS cells transiently transduced with rat GHS1a receptors virus were used. In RC-4B/C cells, GSK1614343 and YIL-781, depressed the ghrelin maximal response in FLIPR assay as result of hemi-equilibria phenomenon. When using the [3H]-IP accumulation assay both compounds behaved as competitive antagonist with pKB values of 8.03 for GSK1614343 and 7.54 for YIL-781. In rat recombinant receptor, GSK1614343 and YIL-781 inhibited the calcium response induced by ghrelin with pIC50 values of 7.90 and 8.27, respectively. GSK1614343 and YIL-781 did not show intrinsic activity in both endogenously expressed and recombinant rat GHS1a receptors. The new ghrelin receptor antagonist GSK1614343 is a potent competitive antagonist in rat pituitary RC-4B/C cells endogenously expressing GHS1a receptors when equilibrium conditions between ligand and receptor are reached in the test assay. GSK1614343 represents a useful tool to investigate the physiological relevance of the ghrelin system in rat models.


Assuntos
Compostos Azabicíclicos/farmacologia , Regulação da Expressão Gênica , Hidrazinas/farmacologia , Pirróis/farmacologia , Receptores de Grelina/antagonistas & inibidores , Receptores de Grelina/genética , Sequência de Aminoácidos , Animais , Baculoviridae/genética , Cálcio/metabolismo , Linhagem Celular Tumoral , Humanos , Fosfatos de Inositol/metabolismo , Dados de Sequência Molecular , Regiões Promotoras Genéticas/genética , Ratos
7.
Bioorg Med Chem Lett ; 17(18): 5218-21, 2007 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-17629700

RESUMO

Corticotropin-releasing factor (CRF), a 41 amino acid peptide neurohormone synthesised by specific hypothalamic nuclei in the brain, is implicated in stress-related function. Antagonism of CRF(1) receptors is an attractive therapeutic approach for the treatment of depression and anxiety. Unsaturated tetrahydrotriazaacenaphthylenes of general structure 3 have been identified as potent and selective CRF(1) receptor antagonists with a suitable oral pharmacokinetic profile.


Assuntos
Naftalenos/farmacologia , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Administração Oral , Humanos , Naftalenos/administração & dosagem , Naftalenos/química , Naftalenos/farmacocinética , Proteínas Recombinantes/antagonistas & inibidores
8.
Bioorg Med Chem Lett ; 16(5): 1342-5, 2006 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-16337118

RESUMO

Exploiting the SAR of the known pyrrole derivatives, a new class of mGluR1 antagonists was developed through a cyclization of the C-2 position on the pyrrole N-1 nitrogen. The resulting pyrrolo[1,2-a]pyrazinones are potent and noncompetitive antagonists.


Assuntos
Pirazinas/química , Pirazinas/farmacologia , Pirróis/química , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Animais , Células CHO , Cricetinae , Concentração Inibidora 50 , Estrutura Molecular , Receptores de Glutamato Metabotrópico/metabolismo , Relação Estrutura-Atividade
11.
Bioorg Med Chem Lett ; 13(13): 2113-8, 2003 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-12798316
12.
Bioorg Med Chem ; 11(2): 171-83, 2003 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-12470711

RESUMO

Metabotropic glutamate receptors (mGluRs) are an unusual family of G-protein coupled receptor (GPCR), and are characterised by a large extracellular N-terminal domain that contains the glutamate binding site. We have identified a new class of non-competitive metabotropic glutamate receptor 1 (mGluR1) antagonists, 2,4-dicarboxy-pyrroles which are endowed with nanomolar potency. They interact within the 7 transmembrane (7TM) domain of the receptor and show antinociceptive properties when tested in a number of different animal models.


Assuntos
Analgésicos não Narcóticos/síntese química , Analgésicos não Narcóticos/farmacologia , Pirróis/síntese química , Pirróis/farmacologia , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Animais , Células CHO , Técnicas de Química Combinatória , Cricetinae , Eletrofisiologia/métodos , Humanos , Concentração Inibidora 50 , Medição da Dor/efeitos dos fármacos , Ligação Proteica , Estrutura Terciária de Proteína , Ratos , Receptores de Glutamato Metabotrópico/química , Receptores de Glutamato Metabotrópico/genética , Proteínas Recombinantes de Fusão/antagonistas & inibidores , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Medula Espinal/efeitos dos fármacos , Medula Espinal/fisiologia , Relação Estrutura-Atividade , Xenopus laevis
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA