RESUMO
High throughput screening of our compound library revealed a series of N-pyridyl-3-benzamides as low micromolar agonists of the human TRPV1 receptor. Synthesis of analogs in this series led to the discovery of a series of N-quinolin-3-yl-benzamides as low nanomolar antagonists of human TRPV1.
Assuntos
Benzamidas/síntese química , Benzamidas/farmacologia , Isoquinolinas/química , Piridinas/química , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/metabolismo , Animais , Benzamidas/química , Benzamidas/uso terapêutico , Reagentes de Ligações Cruzadas/química , Humanos , Hiperalgesia/tratamento farmacológico , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
We report on a series of alpha-substituted-beta-tetralin-derived and related phenethyl-based isoquinolinyl and hydroxynaphthyl ureas as potent antagonists of the human TRPV1 receptor. The synthesis and Structure-activity relationships (SAR) of the series are described.
Assuntos
Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/metabolismo , Tetra-Hidronaftalenos/farmacologia , Ureia/farmacologia , Ligação Competitiva/efeitos dos fármacos , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Canais de Cátion TRPV/química , Tetra-Hidronaftalenos/química , Ureia/análogos & derivados , Ureia/químicaRESUMO
Starting from a low micromolar agonist lead identified by high-throughput screening, series of N-isoquinolin-5-yl-N'-aralkyl ureas and analogous amides were developed as potent antagonists of human vanilloid receptor 1 (VR1). The synthesis and structure-activity relationships (SAR) of the series are described.
Assuntos
Amidas/química , Isoquinolinas/química , Receptores de Droga/antagonistas & inibidores , Ureia/química , Amidas/metabolismo , Linhagem Celular , Humanos , Isoquinolinas/metabolismo , Receptores de Droga/metabolismo , Canais de Cátion TRPV , Ureia/metabolismoRESUMO
The design and synthesis of novel pyrrolidine-containing bradykinin antagonists, II, are described. Conformational analysis suggested that a pyrrolidine moiety could substitute for the N-methyl cis-amide moiety of FR 173657. The in vitro binding data showed that the (S)-isomer of II was potent in the bradykinin B(2) receptor-binding assay with a K(i) of 33 nM. The opposite isomer, (R)-II, had a K(i) of 46 nM. The in vitro binding data confirmed our conformational hypothesis.
Assuntos
Bradicinina/antagonistas & inibidores , Pirrolidinas/síntese química , Pirrolidinas/farmacologia , Desenho de Fármacos , Isomerismo , Modelos Moleculares , Conformação Molecular , Receptores da Bradicinina/metabolismoRESUMO
The synthesis and structure-activity relationships of a novel series of aroylpyrrole alkylamides as potent selective bradykinin B(2) receptor antagonists are described. Several members of this series display nanomolar affinity at the B(2) receptor and show activity in an animal model of antinociception.
