RESUMEN
We report here the first inhibitor-bound structure of a mitotic motor protein. The 1.9 A resolution structure of the motor domain of KSP, bound with the small molecule monastrol and Mg2+ x ADP, reveals that monastrol confers inhibition by "induced-fitting" onto the protein some 12 A away from the catalytic center of the enzyme, resulting in the creation of a previously non-existing binding pocket. The structure provides new insights into the biochemical and mechanical mechanisms of the mitotic motor domain. Inhibition of KSP provides a novel mechanism to arrest mitotic spindle formation, a target of several approved and investigative anti-cancer agents. The structural information gleaned from this novel pocket offers a new angle for the design of anti-mitotic agents.
Asunto(s)
Cinesinas/antagonistas & inhibidores , Cinesinas/química , Pirimidinas/farmacología , Tionas/farmacología , Adenosina Difosfato/química , Adenosina Difosfato/metabolismo , Sitios de Unión , Cristalización , Cristalografía por Rayos X , Humanos , Magnesio/metabolismo , Microtúbulos/química , Mitosis , Modelos Moleculares , Proteínas Motoras Moleculares , Unión Proteica/genética , Conformación Proteica , Estructura Terciaria de Proteína , Relación Estructura-ActividadRESUMEN
3(S)-(6-methoxypyridin-3-yl)-3-[2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)propyl]imidazolidin-1-yl]propionic acid 6 was identified as a potent and selective antagonist of the alpha(v)beta(3) receptor. This compound has an excellent in vitro profile (IC(50) = 0.08 nM), a significant unbound fraction in human plasma (12%), and good pharmacokinetics in rat, dog, and rhesus monkey. On the basis of the efficacy shown in three in vivo models of bone turnover, the compound was selected for clinical development. To support the ongoing metabolism and safety studies, a novel strategy was employed in which a series of oxidized derivatives of 6 were prepared by exposure of 6 (or the methyl ester) to chemical oxidizing agents. These products proved useful in the identification of active metabolites generated by either in vitro or in vivo metabolism.
Asunto(s)
Integrina alfaVbeta3/antagonistas & inhibidores , Naftiridinas/síntesis química , Osteoporosis , Propionatos/síntesis química , Animales , Densidad Ósea/efectos de los fármacos , Resorción Ósea/tratamiento farmacológico , Resorción Ósea/etiología , Resorción Ósea/metabolismo , Perros , Femenino , Humanos , Macaca mulatta , Masculino , Naftiridinas/química , Naftiridinas/farmacología , Osteoporosis/tratamiento farmacológico , Osteoporosis/prevención & control , Ovariectomía , Oxidación-Reducción , Propionatos/química , Propionatos/farmacología , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Two novel series of small-molecule RGD mimetics containing either a substituted pyridone or pyrazinone central constraint were prepared. Modification of the beta-alanine 3-substituent produced compounds that are potent and selective alpha(v)beta(3) antagonists and exhibit a range of physicochemical properties.
Asunto(s)
Integrina alfaVbeta3/antagonistas & inhibidores , Pirazinas/química , Piridonas/química , Alanina/química , Diseño de Fármacos , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Concentración 50 Inhibidora , Imitación Molecular , Oligopéptidos , Unión Proteica , Pirazinas/farmacocinética , Piridonas/farmacocinética , Radioinmunoensayo , Relación Estructura-ActividadRESUMEN
A series of alphaVbeta3 receptor antagonists lacking the amide bond of previously-reported 'chain-shortened' compounds is described. Replacement of the lone amide bond with two methylene groups in this series yields more lipophilic compounds that have longer half-lives, lower clearance, and greater oral bioavailability when administered to dogs.
Asunto(s)
Bencenosulfonatos/química , Bencenosulfonatos/farmacocinética , Integrina alfaVbeta3/antagonistas & inhibidores , Yodobencenos/química , Yodobencenos/farmacocinética , Animales , Perros , Humanos , Integrina alfaVbeta3/metabolismoRESUMEN
Subtle modifications were incorporated into the structure of clinical candidate 1. These changes were designed to maintain potency and selectivity while inducing changes in physical properties leading to improved pharmacokinetics in three species. This approach led to the identification of 4 as a potent, selective alphaVbeta3 receptor antagonist that was selected for clinical development based on an improved PK profile and efficacy demonstrated in an in vivo model of bone turnover.