RESUMEN
4-Acetylamino-2-(3,5-dimethylpyrazol-1-yl)-pyrimidines bearing substituted pyridyl groups as C-6 substituents were prepared as selective adenosine hA2A receptor antagonists for the treatment of Parkinson's disease. The 5-methoxy-3-pyridyl derivative 6g (hA2A Ki 2.3 nM, hA1 Ki 190 nM) was orally active at 3 mg/kg in a rat HIC model but exposure was poor in nonrodent species, presumably due to poor aqueous solubility. Follow-on compound 16a (hA2A Ki 0.83 nM, hA1 Ki 130 nM), bearing a 6-(morpholin-4-yl)-2-pyridyl substituent at C-6, had improved solubility and was orally efficacious (3 mg/kg, HIC) but showed time-dependent cytochrome P450 3A4 inhibition, possibly related to morpholine ring metabolism. Compound 16j (hA2A Ki 0.44 nM, hA1 Ki 80 nM), bearing a 6-(4-methoxypiperidin-1-yl)-2-pyridyl substituent at C-6, was sparingly soluble but had good oral exposure in rodent and nonrodent species, had no cytochrome P450 or human ether-a-go-go related gene channel issues, and was orally efficacious at 1 mg/kg in HIC and at 3 mg/kg for potentiation of l-dopa-induced contralateral rotations in 6-hydroxydopamine-lesioned rats.
Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Enfermedad de Parkinson/tratamiento farmacológico , Pirazoles/farmacología , Pirimidinas/farmacología , Animales , Catalepsia/inducido químicamente , Catalepsia/tratamiento farmacológico , Modelos Animales de Enfermedad , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Haloperidol , Humanos , Ligandos , Estructura Molecular , Pirazoles/síntesis química , Pirazoles/química , Pirimidinas/síntesis química , Pirimidinas/química , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
In recent years, beta-hairpin peptides have been studied in great detail. Much of the focus has been on the thermodynamic stability of beta-hairpin structure. Structural measurements have been conducted with nuclear magnetic resonance, with additional information obtained from circular dichroism, Fourier transform infrared, and molecular dynamic simulation studies. Point mutations, both in the beta-strands and in the turn region, have systematically explored the role of turn sequence, side-chain-side-chain interactions, intramolecular hydrogen bonding, and beta-strand length on beta-hairpin peptide conformational stability. In addition to studying the elements of structural stability independently, the cooperative nature of the individual components to combine to form the overall structure has also been investigated. Because the beta-hairpin peptides often spontaneously form their conformation, they have begun to serve as models for studying peptide binding and therapeutic agents.