RESUMO
The synthesis, in vitro properties, and in vivo pharmacokinetics for a series of sulfoximine-substituted trifluoromethylpyrimidines as inhibitors of proline-rich tyrosine kinase, a target for the possible treatment of osteoporosis, are described. These compounds were prepared as surrogates of the corresponding sulfone compound 1. Sulfone 1 was an attractive PYK2 lead compound; however, subsequent studies determined this compound possessed high dofetilide binding, which is an early indicator of cardiovascular safety. Surprisingly, the corresponding sulfoximine analogs displayed significantly lower dofetilide binding, which, for N-methylsulfoximine (S)-14a, translated to lower activity in a patch clamp hERG K(+) ion channel screen. In addition, compound (S)-14a shows good oral exposure in a rat pharmacokinetic model.
Assuntos
Canais de Potássio Éter-A-Go-Go/metabolismo , Quinase 2 de Adesão Focal/antagonistas & inibidores , Pirimidinas/química , Pirimidinas/farmacologia , Administração Oral , Animais , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Humanos , Iminas/química , Osteoporose/tratamento farmacológico , Técnicas de Patch-Clamp , Fenetilaminas , Pirimidinas/farmacocinética , Ratos , Relação Estrutura-Atividade , Sulfonamidas , Sulfonas/químicaRESUMO
The synthesis and SAR for a series of diaminopyrimidines as PYK2 inhibitors are described. Using a combination of library and traditional medicinal chemistry techniques, a FAK-selective chemical series was transformed into compounds possessing good PYK2 potency and 10- to 20-fold selectivity against FAK. Subsequent studies found that the majority of the compounds were positive in a reactive metabolite assay, an indicator for potential toxicological liabilities. Based on the proposed mechanism for bioactivation, as well as a combination of structure-based drug design and traditional medicinal chemistry techniques, a follow-up series of PYK2 inhibitors was identified that maintained PYK2 potency, FAK selectivity and HLM stability, yet were negative in the RM assay.
Assuntos
Quinase 2 de Adesão Focal/antagonistas & inibidores , Pirimidinas/síntese química , Pirimidinas/farmacologia , Animais , Técnicas de Química Combinatória , Cristalografia por Raios X , Modelos Animais de Doenças , Desenho de Fármacos , Proteína-Tirosina Quinases de Adesão Focal/antagonistas & inibidores , Humanos , Conformação Molecular , Estrutura Molecular , Osteoporose/tratamento farmacológico , Pirimidinas/química , Ratos , Relação Estrutura-AtividadeRESUMO
The synthesis, biological activity, and pharmacokinetic profile of CCR1 antagonists are described.
Assuntos
Piperazinas/química , Piperazinas/metabolismo , Receptores de Quimiocinas/antagonistas & inibidores , Animais , Cães , Haplorrinos , Humanos , Microssomos Hepáticos/metabolismo , Piperazinas/síntese química , Ratos , Receptores CCR1RESUMO
The present manuscript details structure-activity relationship studies of lead structure 1, which led to the discovery of CCR1 antagonists >100-fold more potent than 1.
Assuntos
Receptores de Quimiocinas/antagonistas & inibidores , Linhagem Celular , Humanos , Receptores CCR1 , Relação Estrutura-AtividadeRESUMO
The synthesis, biological activity, and pharmacokinetic profile of novel CCR1 antagonists are described.
Assuntos
Receptores de Quimiocinas/antagonistas & inibidores , Animais , Cães , Haplorrinos , Farmacocinética , Receptores CCR1RESUMO
The chemokines CCL3 and CCL5, as well as their shared receptor CCR1, are believed to play a role in the pathogenesis of several inflammatory diseases including rheumatoid arthritis, multiple sclerosis, and transplant rejection. In this study we describe the pharmacological properties of a novel small molecular weight CCR1 antagonist, CP-481,715 (quinoxaline-2-carboxylic acid [4(R)-carbamoyl-1(S)-(3-fluorobenzyl)-2(S),7-dihydroxy-7-methyloctyl]amide). Radiolabeled binding studies indicate that CP-481,715 binds to human CCR1 with a Kd of 9.2 nm and displaces 125I-labeled CCL3 from CCR1-transfected cells with an IC50 of 74 nm. CP-481,715 lacks intrinsic agonist activity but fully blocks the ability of CCL3 and CCL5 to stimulate receptor signaling (guanosine 5'-O-(thiotriphosphate) incorporation; IC50 = 210 nm), calcium mobilization (IC50 = 71 nm), monocyte chemotaxis (IC50 = 55 nm), and matrix metalloproteinase 9 release (IC50 = 54 nm). CP-481,715 retains activity in human whole blood, inhibiting CCL3-induced CD11b up-regulation and actin polymerization (IC50 = 165 and 57 nm, respectively) on monocytes. Furthermore, it behaves as a competitive and reversible antagonist. CP-481,715 is >100-fold selective for CCR1 as compared with a panel of G-protein-coupled receptors including related chemokine receptors. Evidence for its potential use in human disease is suggested by its ability to inhibit 90% of the monocyte chemotactic activity present in 11/15 rheumatoid arthritis synovial fluid samples. These data illustrate that CP-481,715 is a potent and selective antagonist for CCR1 with therapeutic potential for rheumatoid arthritis and other inflammatory diseases.