RESUMO
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.
Assuntos
Benzenossulfonatos/química , Benzenossulfonatos/farmacocinética , Integrina alfaVbeta3/antagonistas & inibidores , Iodobenzenos/química , Iodobenzenos/farmacocinética , Animais , Cães , Humanos , Integrina alfaVbeta3/metabolismoRESUMO
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.
Assuntos
Integrina alfaVbeta3/antagonistas & inibidores , Naftiridinas/química , Animais , Cães , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Integrina alfaVbeta3/metabolismo , Macaca mulatta , Masculino , Naftiridinas/metabolismo , Naftiridinas/farmacologia , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , RatosRESUMO
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.
Assuntos
Cinesinas/antagonistas & inibidores , Cinesinas/química , Pirimidinas/farmacologia , Tionas/farmacologia , Difosfato de Adenosina/química , Difosfato de Adenosina/metabolismo , Sítios de Ligação , Cristalização , Cristalografia por Raios X , Humanos , Magnésio/metabolismo , Microtúbulos/química , Mitose , Modelos Moleculares , Proteínas Motores Moleculares , Ligação Proteica/genética , Conformação Proteica , Estrutura Terciária de Proteína , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Integrina alfaVbeta3/antagonistas & inibidores , Naftiridinas/síntese química , Osteoporose , Propionatos/síntese química , Animais , Densidade Óssea/efeitos dos fármacos , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/etiologia , Reabsorção Óssea/metabolismo , Cães , Feminino , Humanos , Macaca mulatta , Masculino , Naftiridinas/química , Naftiridinas/farmacologia , Osteoporose/tratamento farmacológico , Osteoporose/prevenção & controle , Ovariectomia , Oxirredução , Propionatos/química , Propionatos/farmacologia , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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.