RESUMO
A series of potent PDGFR inhibitors has been identified. The series was optimized for duration of action in the lung. A novel kinase occupancy assay was used to directly measure target occupancy after i.t. dosing. Compound 25 shows 24 h occupancy of the PDGFR kinase domain, after a single i.t. dose and has efficacy at 0.03 mg/kg, in the rat moncrotaline model of pulmonary arterial hypertension. Examination of PK/PD data from the optimization effort has revealed in vitro:in vivo correlations which link duration of action in vivo with low permeability and high basicity and demonstrate that nonspecific binding to lung tissue increases with lipophilicity.
Assuntos
Remodelação das Vias Aéreas/efeitos dos fármacos , Hipertensão Pulmonar/tratamento farmacológico , Niacinamida/análogos & derivados , Pirazóis/química , Receptores do Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Remodelação Vascular/efeitos dos fármacos , Administração por Inalação , Animais , Linhagem Celular , Proliferação de Células , Hipertensão Pulmonar/patologia , Pulmão/irrigação sanguínea , Membranas Artificiais , Simulação de Acoplamento Molecular , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/patologia , Niacinamida/síntese química , Niacinamida/química , Niacinamida/farmacologia , Permeabilidade , Proteínas Proto-Oncogênicas c-kit/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-kit/química , Pirazóis/síntese química , Pirazóis/farmacologia , Ratos , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/química , Receptor beta de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Receptor beta de Fator de Crescimento Derivado de Plaquetas/química , Receptores do Fator de Crescimento Derivado de Plaquetas/química , Relação Estrutura-AtividadeRESUMO
A D(3)-symmetric knotted cyclophane, with a subgraph of trefoil topology, was synthesized by cyclization of a D(3)-symmetric scaffold. Control of configuration at the three metal-based stereocenters arises from a bascule/pivot mechanism.
Assuntos
Técnicas de Química Sintética , Éteres Cíclicos/química , Éteres Cíclicos/síntese química , Modelos Moleculares , Conformação Molecular , Estereoisomerismo , Especificidade por SubstratoRESUMO
Concatenated macrocycles containing manisyl-substituted tridentate ligands 2,2':6',2''-terpyridine and 2-pyridin-2-yl-1,10-phenanthroline (simply referred to as terpyridine and pyridyl-phenanthroline herein) have been prepared via dual cyclization procedures. The manisyl derivative (manisyl = 4-methoxy-2,6-dimethylphenyl) was chosen for its ability to improve solubility while simultaneously incorporating functionality. Deprotection of the methoxy groups provided a soluble ligand that was re-alkylated with an array of terminal alkyne and alkene linkers. The tridentate coordinating ability of these ligands enabled complexation with Ru(ii) and Fe(ii), generating achiral and racemic octahedral complexes for terpyridine and pyridyl-phenanthroline, respectively. Subsequent macrocyclization via olefin metathesis or copper-mediated alkyne coupling afforded the corresponding catenanes, and in some cases a figure-eight macrocycle. The difference in symmetry and the presence of the manisyl group allowed the distinction between the catenane and the undesired figure-eight to be made directly by (1)H NMR. Metal-free achiral and racemic catenanes were obtained by liberating Fe(ii) from the octahedral bound title ligands by treatment with hydrogen peroxide.