RESUMO
Activation of CCR8 by its ligand CCL1 may play an important role in diseases such as asthma, multiple sclerosis, and cancer. The study of small molecule CCR8 antagonists will help establish the validation of these hypotheses. We report the design, synthesis, and progress toward optimization of potent small molecule CCR8 antagonists identified from a high-throughput screen. These analogues exhibit good potency in binding and chemotaxis assays, show good selectivity versus the hERG channel, and have good eADME (early absorption, distribution, metabolism, and excretion) profiles.
Assuntos
Desenho de Fármacos , Receptores de Quimiocinas/antagonistas & inibidores , Aminação , Linhagem Celular , Quimiotaxia/efeitos dos fármacos , Éter/química , Humanos , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Piperidinas/farmacologia , Pirrolidinas/síntese química , Pirrolidinas/química , Pirrolidinas/farmacologia , Receptores CCR8 , Relação Estrutura-AtividadeRESUMO
The identification, optimization, and structure-activity relationship (SAR) of small-molecule CCR4 antagonists is described. An initial screening hit with micromolar potency was identified that was optimized to sub-micromolar binding potency by enantiomer resolution, halogenation of the naphthalene ring, and extension of the alkyl chain linker between the central piperidine ring and the terminal aryl group. An antagonist was identified that showed good cross-reactivity against the mouse receptor and inhibited CCR4-based cell recruitment in dose-dependent fashion.
Assuntos
Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Naftalenos/química , Naftalenos/farmacologia , Receptores de Quimiocinas/antagonistas & inibidores , Sulfonamidas/química , Sulfonamidas/farmacologia , Animais , Anti-Inflamatórios não Esteroides/síntese química , Camundongos , Camundongos Endogâmicos BALB C , Naftalenos/síntese química , Receptores CCR4 , Relação Estrutura-Atividade , Sulfonamidas/síntese químicaRESUMO
4-[4-(N-Substituted-thio-carbamoyl)-1-piperazinyl]-6-methoxy-7-alkoxyamino-quinazoline derivatives such as 14 (CT53986) have been identified to be potent and selective inhibitors of the phosphorylation of PDGFR. SAR-investigations are described in the arylamine segment, C-7 appendage, and the thiourea moiety. Bioisosteres of thiourea (cyanoguanidine), and of quinazoline (quinoline-3-carbonitrile) were synthesized and are compared for their in vitro inhibitory activity. PK profiles of the optimized compounds in rat, dog, and cynomolgus monkey are described.