RESUMEN
The synthesis and CRF receptor binding affinities of several new series of N-aryltriazolo- and -imidazopyrimidines and -pyridines are described. These cyclized systems were prepared from appropriately substituted diaminopyrimidines or -pyridines by nitrous acid, orthoester, or acyl halide treatment. Variations of amino (ether) pendants and aromatic substituents have defined the structure-activity relationships of these series and resulted in the identification of a variety of high-affinity agents (Ki's < 10 nM). On the basis of this property and lipophilicity differences, six of these compounds (4d,i,n,x, 8k, 9a) were initially chosen for rat pharmacokinetic (PK) studies. Good oral bioavailability, high plasma levels, and duration of four of these compounds (4d,i,n,x) prompted further PK studies in the dog following both iv and oral routes of administration. Results from this work indicated 4i,x had properties we believe necessary for a potential therapeutic agent, and 4i1 has been selected for further pharmacological studies that will be reported in due course.
Asunto(s)
Piridinas/metabolismo , Piridinas/farmacocinética , Pirimidinas/metabolismo , Pirimidinas/farmacocinética , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Administración Oral , Animales , Disponibilidad Biológica , Línea Celular , Perros , Humanos , Ratones , Piridinas/síntesis química , Piridinas/química , Pirimidinas/síntesis química , Pirimidinas/química , Ratas , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Proteínas Recombinantes/metabolismo , Relación Estructura-ActividadRESUMEN
Purification of oligonucleotides by HPLC is limited by association between failure sequences and full-length oligonucleotide. We describe a protocol for denaturing purification of 5'-dimethoxytritylated oligonucleotides that ensures that separation of tritylated and non-tritylated species will not be complicated by strand association. Fully denaturing conditions are produced by the use of tetraethylammonium hydroxide, which is a basic reagent with ion-pairing properties similar to triethylammonium acetate. The method also includes two other convenient features: a) the option of loading the crude oligonucleotide without removing concentrated ammonium hydroxide and b) detritylation on the column with separation of dimethoxytrityl alcohol.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Oligodesoxirribonucleótidos/aislamiento & purificación , Secuencia de Bases , Biotecnología , Estudios de Evaluación como Asunto , Datos de Secuencia Molecular , Desnaturalización de Ácido Nucleico , Oligodesoxirribonucleótidos/síntesis química , Oligodesoxirribonucleótidos/química , Polidesoxirribonucleótidos/síntesis química , Polidesoxirribonucleótidos/química , Polidesoxirribonucleótidos/aislamiento & purificación , Tetraetilamonio , Compuestos de TetraetilamonioRESUMEN
A series of 4-aryl-2-(N-ethylanilino)pyrimidines has been synthesized as corticotropin-releasing hormone (CRH) inhibitors. The effect of substitution on each aromatic ring on receptor binding was investigated.