RESUMO
Efforts to optimize biological activity, novelty, selectivity and oral bioavailability of Mps1 inhibitors, from a purine based lead MPI-0479605, are described in this Letter. Mps1 biochemical activity and cytotoxicity in HCT-116 cell line were improved. On-target activity confirmation via mechanism based G2/M escape assay was demonstrated. Physico-chemical and ADME properties were optimized to improve oral bioavailability in mouse.
Assuntos
Adenina/análogos & derivados , Morfolinas/química , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Purinas/química , Adenina/química , Adenina/farmacocinética , Adenina/toxicidade , Administração Oral , Animais , Apoptose/efeitos dos fármacos , Sítios de Ligação , Cristalografia por Raios X , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Células HCT116 , Humanos , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Camundongos , Conformação Molecular , Morfolinas/farmacocinética , Morfolinas/toxicidade , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/toxicidade , Proteínas Serina-Treonina Quinases/metabolismo , Relação Estrutura-AtividadeRESUMO
In the title compound, C(17)H(16)O(2), the dihedral angle between the aromatic rings is 5.12â (13)° and an intra-molecular O-Hâ¯O hydrogen bond generates an S(6) ring.
RESUMO
The mol-ecule of the title compound, C(17)H(16)O(3), exists in the E conformation with respect to the central C=C bond, is almost planar(r.m.s. deviation = 0.003â Å) and has an intra-molecular O-Hâ¯O hydrogen bond, which generates an S(6) ring. In the crystal, mol-ecules are linked by C-Hâ¯O inter-actions.
RESUMO
In the structure of the title compound, C(15)H(14)O(2)S, the benzene ring is nearly coplanar with the thio-phene ring. The hydroxy group substituted at C2 position is in an antiperi-planar conformation with respect to the phenyl ring. The crystal structure exhibits weak intramolecular O-Hâ¯O hydrogen bonding.