RESUMEN
We have previously reported that optimization of a series of phenylacetic acid derivatives led to the discovery of CRTH2 and DP dual antagonists, such as AMG 009 and AMG 853. During the optimization process, we discovered that minor structural modifications also afforded potent and selective CRTH2 or DP antagonists. Here we report the structure-activity relationship that led to the discovery of selective CRTH2 antagonists such as 2 and 17, and selective DP antagonists, such as 4 and 5.
Asunto(s)
Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Asma/terapia , Química Farmacéutica/métodos , Diseño de Fármacos , Humanos , Hipersensibilidad/tratamiento farmacológico , Concentración 50 Inhibidora , Cinética , Modelos Químicos , Fenilacetatos/química , Fenilacetatos/farmacología , Prostaglandina D2/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Sulfonamidas/química , Sulfonamidas/farmacologíaRESUMEN
Our first generation CRTH2 and DP dual antagonists, represented by AMG 009, are more potent toward the CRTH2 receptor than to the DP receptor. Here we report our efforts in the discovery of CRTH2 and DP dual antagonists with more balanced potencies to both receptors, such as compound 15.
Asunto(s)
Diseño de Fármacos , Fenilacetatos/síntesis química , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Células HEK293 , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Fenilacetatos/química , Fenilacetatos/farmacología , Unión Proteica/efectos de los fármacosRESUMEN
We studied coordination across body parts in throwing during adaptation to prisms. Human subjects threw balls at a target before, during, and after wearing laterally shifting prism eyeglasses. Positions of head, shoulders, arm, and ball were video-recorded continuously. We computed body angles of eyes-in-head, head-on-trunk, trunk-on-arm, and arm-on-ball. In each subject, the gaze-throw adjustment during adaptation was distributed across all sets of coupled body parts. The distribution of coupling changed unpredictably from throw to throw within a single session. The angular variation among coupled body parts was typically significantly larger than angular variation of on-target hits. Thus coupled body parts changed interdependently to account for the high accuracy of ball-on-target. Principal components and Monte Carlo analyses showed variability in body angles across throws with a wide range of variability/stereotypy across subjects. The data support a model of a dynamic and generalized solution as evidenced by the distribution of the gaze-throw adjustment across body parts.