RESUMO
Transient-receptor-potential melastatin 8 (TRPM8), the predominant mammalian cold-temperature thermosensor, is a nonselective cation channel expressed in a subpopulation of sensory neurons in the peripheral nervous system, including nerve circuitry implicated in migraine pathogenesis: the trigeminal and pterygopalatine ganglia. Genomewide association studies have identified an association between TRPM8 and reduced risk of migraine. This disclosure focuses on medicinal-chemistry efforts to improve the druglike properties of initial leads, particularly removal of CYP3A4-induction liability and improvement of pharmacokinetic properties. A novel series of biarylmethanamide TRPM8 antagonists was developed, and a subset of leads were evaluated in preclinical toxicology studies to identify a clinical candidate with an acceptable preclinical safety profile leading to clinical candidate AMG 333, a potent and highly selective antagonist of TRPM8 that was evaluated in human clinical trials.
Assuntos
Anticonvulsivantes/farmacologia , Descoberta de Drogas , Transtornos de Enxaqueca/prevenção & controle , Niacina/química , Convulsões/tratamento farmacológico , Canais de Cátion TRPM/antagonistas & inibidores , Animais , Anticonvulsivantes/química , Agonistas dos Canais de Cálcio/toxicidade , Humanos , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Modelos Moleculares , Estrutura Molecular , Pirimidinonas/toxicidade , Ratos , Ratos Sprague-Dawley , Convulsões/induzido quimicamenteRESUMO
Transient receptor potential melastatin 8 (TRPM8) is a nonselective cation channel expressed in a subpopulation of sensory neurons in the peripheral nervous system. TRPM8 is the predominant mammalian cold temperature thermosensor and is activated by cold temperatures ranging from 8 to 25 °C and cooling compounds such as menthol or icilin. TRPM8 antagonists are being pursued as potential therapeutics for treatment of pain and bladder disorders. This manuscript outlines new developments in the SAR of a lead series of 1,2,3,4-tetrahydroisoquinoline derivatives with emphasis on strategies to improve pharmacokinetic properties and potency. Selected compounds were profiled in two TRPM8 target-specific in vivo coverage models in rats (the icilin-induced wet dog shake model and the cold pressor test). Compound 45 demonstrated robust efficacy in both pharmacodynamic models with ED90 values <3 mg/kg.
Assuntos
Comportamento Animal/efeitos dos fármacos , Microssomos Hepáticos/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Canais de Cátion TRPM/antagonistas & inibidores , Tetra-Hidroisoquinolinas/farmacocinética , Animais , Dicroísmo Circular , Temperatura Baixa , Cães , Humanos , Masculino , Microssomos Hepáticos/metabolismo , Pirimidinonas/farmacologia , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Estereoisomerismo , Canais de Cátion TRPM/metabolismo , Tetra-Hidroisoquinolinas/química , Tetra-Hidroisoquinolinas/farmacologia , Distribuição TecidualRESUMO
The membrane bound large-conductance, calcium-activated potassium channel (BKCa) is an important regulator of neuronal activity. Here we describe the identification and structure-activity relationship of a novel class of potent tetrahydroquinoline BKCa agonists. An example from this class of BKCa agonists was shown to depress the spontaneous neuronal discharges in an electrophysiological model of migraine.
Assuntos
Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/agonistas , Neurônios/efeitos dos fármacos , Quinolinas/química , Quinolinas/farmacologia , Animais , Células CHO , Cricetinae , Cricetulus , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Humanos , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/patologia , Modelos Biológicos , Ratos , Relação Estrutura-Atividade , Núcleos do Trigêmeo/citologiaRESUMO
A novel series of 4,5-biarylimidazoles as TRPV1 antagonists were designed based on the previously reported 4,6-disubstituted benzimidazole series. The analogs were evaluated for their ability to block capsaicin- or acid-induced calcium influx in TRPV1-expressing CHO cells. These studies led to the identification of a highly potent and orally bioavailable TRPV1 antagonist, imidazole 33.
Assuntos
Imidazóis/química , Imidazóis/farmacologia , Canais de Cátion TRPV/antagonistas & inibidores , Administração Oral , Animais , Células CHO , Cricetinae , Cricetulus , Imidazóis/administração & dosagem , Imidazóis/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
The vanilloid receptor-1 (VR1 or TRPV1) is a membrane-bound, nonselective cation channel that is predominantly expressed by peripheral neurons sensing painful stimuli. TRPV1 antagonists produce antihyperalgesic effects in animal models of inflammatory and neuropathic pain. Herein, we describe the synthesis and the structure-activity relationships of a series of 2-(4-pyridin-2-ylpiperazin-1-yl)-1H-benzo[d]imidazoles as novel TRPV1 antagonists. Compound 46ad was among the most potent analogues in this series. This compound was orally bioavailable in rats and was efficacious in blocking capsaicin-induced flinch in rats in a dose-dependent manner. Compound 46ad also reversed thermal hyperalgesia in a model of inflammatory pain, which was induced by complete Freund's adjuvant (CFA).
