RESUMEN
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.