RESUMEN
CEP-32215 is a new, potent, selective, and orally bioavailable inverse agonist of the histamine H3 receptor (H3R) with drug-like properties. High affinity in human (hH3R Ki = 2.0 ± 0.2 nM) and rat (rH3R Ki = 3.6 ± 0.7 nM) H3R radioligand binding assays was demonstrated. Potent functional antagonism (Kb = 0.3 ± 0.1 nM) and inverse agonism (EC50 = 0.6 ± 0.2 nM) were demonstrated in [(35)S]guanosine 5(')-O-(γ-thio)-triphosphate binding assays. Oral bioavailability and dose-related exposure was consistent among rat, dog, and monkey. After oral dosing, occupancy of H3R by CEP-32215 was estimated by the inhibition of ex vivo binding in rat cortical slices (ED50 = 0.1 mg/kg p.o.). Functional antagonism in brain was demonstrated by the inhibition of R-α-methylhistamine-induced drinking in the rat dipsogenia model (ED50 = 0.92 mg/kg). CEP-32215 significantly increased wake duration in the rat EEG model at 3-30 mg/kg p.o. Increased motor activity, sleep rebound or undesirable events (such as spike wave or seizure activity) was not observed following doses up to 100 mg/kg p.o., indicating an acceptable therapeutic index. CEP-32215 may have potential utility in the treatment of a variety of sleep disorders. This article is part of the Special Issue entitled 'Histamine Receptors'.
Asunto(s)
Agonismo Inverso de Drogas , Antagonistas de los Receptores Histamínicos H3/farmacología , Piperidinas/farmacología , Pirazinas/farmacología , Compuestos de Espiro/farmacología , Vigilia/efectos de los fármacos , Administración Oral , Animales , Disponibilidad Biológica , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Perros , Ingestión de Líquidos/efectos de los fármacos , Ingestión de Líquidos/fisiología , Evaluación Preclínica de Medicamentos , Agonistas de los Receptores Histamínicos/farmacología , Antagonistas de los Receptores Histamínicos H3/farmacocinética , Humanos , Macaca fascicularis , Masculino , Metilhistaminas/farmacología , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Piperidinas/farmacocinética , Pirazinas/farmacocinética , Ratas Sprague-Dawley , Receptores Histamínicos H3/metabolismo , Sueño/efectos de los fármacos , Sueño/fisiología , Compuestos de Espiro/farmacocinética , Vigilia/fisiologíaRESUMEN
A series of fused cyclopropyl-4,5-dihydropyridazin-3-one (3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one) phenoxypiperidine analogs was designed and synthesized, leading to the identification of (1R,6S)-5-[4-(1-cyclobutyl-piperidin-4-yloxy)-phenyl]-3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one (R,S-4a) as a second-generation pyridazin-3-one H3R antagonist. Compound R,S-4a was a potent H3R functional antagonist in vivo in the rat dipsogenia model, demonstrated potent wake activity in the rat EEG/EMG model, and enhanced short-term memory in the rat social recognition memory model at doses as low as 0.03-0.3 mg/kg po.
Asunto(s)
Nootrópicos/química , Piperidinas/química , Piridazinas/química , Receptores Histamínicos H3/química , Animales , Trastornos del Conocimiento/tratamiento farmacológico , Modelos Animales de Enfermedad , Perros , Evaluación Preclínica de Medicamentos , Agonismo Inverso de Drogas , Semivida , Haplorrinos , Memoria a Corto Plazo/efectos de los fármacos , Nootrópicos/farmacocinética , Nootrópicos/farmacología , Nootrópicos/uso terapéutico , Piperidinas/farmacocinética , Piperidinas/farmacología , Piperidinas/uso terapéutico , Piridazinas/farmacocinética , Piridazinas/farmacología , Piridazinas/uso terapéutico , Ratas , Receptores Histamínicos H3/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A substantial body of evidence supports the utility of antiangiogenesis inhibitors as a strategy to block or attenuate tumor-induced angiogenesis and inhibition of primary and metastatic tumor growth in a variety of solid and hematopoietic tumors. Given the requirement of tumors for different cytokine and growth factors at distinct stages of their growth and dissemination, optimal antiangiogenic therapy necessitates inhibition of multiple, complementary, and nonredundant angiogenic targets. 11-(2-Methylpropyl)-12,13-dihydro-2-methyl-8-(pyrimidin-2-ylamino)-4H-indazolo[5,4-a]pyrrolo[3,4-c]carbazol-4-one (11b, CEP-11981) is a potent orally active inhibitor of multiple targets (TIE-2, VEGF-R1, 2, and 3, and FGF-R1) having essential and nonredundant roles in tumor angiogenesis and vascular maintenance. Outlined in this article are the design strategy, synthesis, and biochemical and pharmacological profile for 11b, which completed Phase I clinical assessing safety and pharmacokinetics allowing for the initiation of proof of concept studies.