RESUMO
Imidazo-[1, 2-a]pyrazine 1 is a potent inhibitor of Aurora A and B kinase in vitro and is effective in in vivo tumor models, but has poor oral bioavailbility and is unsuitable for oral dosing. We describe herein our effort to improve oral exposure in this class, resulting ultimately in the identification of a potent Aurora inhibitor 16, which exhibited good drug exposure levels across species upon oral dosing, and showed excellent in vivo efficacy in a mouse xenograft tumor model when dosed orally.
Assuntos
Antineoplásicos/uso terapêutico , Aurora Quinase A/antagonistas & inibidores , Aurora Quinase B/antagonistas & inibidores , Imidazóis/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazinas/uso terapêutico , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Cães , Células HCT116 , Haplorrinos , Histonas/metabolismo , Humanos , Imidazóis/administração & dosagem , Imidazóis/síntese química , Imidazóis/farmacocinética , Camundongos , Fosforilação , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Pirazinas/administração & dosagem , Pirazinas/síntese química , Pirazinas/farmacocinética , Ratos , Estereoisomerismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The structure-activity relationships of new Aurora A/B kinase inhibitors derived from the previously identified kinase inhibitor 12 are described. Introduction of acetic acid amides onto the pyrazole of compound 12 was postulated to influence Aurora A/B selectivity and improve the profile against off-target kinases. The SAR of the acetic acid amides was explored and the effect of substitution on enzyme inhibition as well as mechanism-based cell activity was studied. Additionally, several of the more potent inhibitors were screened for their off-target kinase selectivity.
Assuntos
Imidazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirazinas/farmacologia , Aurora Quinases , Cristalografia por Raios X , Modelos Moleculares , Relação Estrutura-AtividadeRESUMO
We report a series of potent imidazo[1,2-a]pyrazine-based Aurora kinase inhibitors. Optimization of the solvent accessible 8-position led to improvements in both oral bioavailability and off-target kinase inhibition. Compound 25 demonstrates anti-tumor activity in an A2780 ovarian tumor xenograft model.
Assuntos
Imidazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirazinas/farmacologia , Administração Oral , Animais , Aurora Quinases , Disponibilidade Biológica , Linhagem Celular Tumoral , Feminino , Humanos , Imidazóis/química , Imidazóis/farmacocinética , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Pirazinas/química , Pirazinas/farmacocinética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A homogeneous organometallic Ir complex was shown to catalyze the electro-oxidation of 4-methoxybenzyl alcohol to p-anisaldehyde at a very low applied potential with remarkably high selectivity and Faradaic efficiency. In the chemical catalysis, when stoichiometric oxidant and anionic base were used to separately accept electrons and protons, aldehyde selectivity was in agreement with electrolysis results.
RESUMO
A chiral copper-hydride catalyst for the asymmetric conjugate reduction of alpha,beta-unsaturated carbonyl compounds has been used for the reduction of substrates containing beta-nitrogen substituents. A new set of reaction conditions has allowed for a variety of beta-azaheterocyclic acid derivatives to be synthesized in excellent yields and with high degrees of enantioselectivity. In addition, the effect that the nature of the nitrogen substituent has on the rate of the conjugate reduction reaction has been explored.
Assuntos
Cobre/química , Compostos Heterocíclicos/síntese química , Ácidos/síntese química , CatáliseRESUMO
A novel palladium-catalyzed arylation of ketone enolates with o-nitrohaloarenes was achieved through the addition of phenol additives. The mild reaction conditions employed allowed for the inclusion of a wide variety of functional groups in both substrates to be tolerated. The products of this reaction were then readily reductively cyclized to give highly substituted indoles in moderate to excellent overall yields.
Assuntos
Indóis/síntese química , Cetonas/química , Fenóis/química , Derivados de Benzeno/química , Bromobenzenos/química , Catálise , Hidrocarbonetos Halogenados/química , Compostos Organometálicos/química , Paládio/químicaRESUMO
A catalyst system for the preparation of biaryls containing four ortho substituents via Suzuki coupling is described. The combination of a catalytic quantity of Pd2(dba)3 with either an electron-rich biarylphosphine or DPEPhos is effective using a wide range of substrates. The X-ray crystal structure of (dba)Pd(2-(9-phenanthryl)phenyl-dicyclohexylphosphine), in which the Pd is coordinated to the 9,10-double bond of the phenanthryl group, is also reported.