RESUMO
BACKGROUND: Expression of the T-cell-associated chemokine receptor CCR8 and its ligand CCL1 have been demonstrated to be elevated in patients with asthma. CCR8 deficiency or inhibition in models of allergic airway disease in mice resulted in conflicting data. OBJECTIVE: To investigate the effects of a selective small molecule CCR8 inhibitor (ML604086) in a primate model of asthma. METHODS: ML604086 and vehicle were administered by intravenous infusion to 12 cynomolgus monkeys during airway challenge with Ascaris suum. Samples were collected throughout the study to measure pharmacokinetics (PK) and systemic CCR8 inhibition, as well as inflammation, T helper 2 (Th2) cytokines and mucus in bronchoalveolar lavage (BAL). Airway resistance and compliance were measured before and after allergen challenge, and in response to increasing concentrations of methacholine. RESULTS: ML604086 inhibited CCL1 binding to CCR8 on circulating T-cells>98% throughout the duration of the study. However, CCR8 inhibition had no significant effect on allergen-induced BAL eosinophilia and the induction of the Th2 cytokines IL-4, IL-5, IL-13 and mucus levels in BAL. Changes in airway resistance and compliance induced by allergen provocation and increasing concentrations of methacholine were also not affected by ML604086. CONCLUSIONS: These results clearly demonstrate a dispensable role for CCR8 in ameliorating allergic airway disease in atopic primates, and suggest that strategies other than CCR8 antagonism should be considered for the treatment of asthma.
Assuntos
Resistência das Vias Respiratórias/fisiologia , Asma/imunologia , Fatores Biológicos/farmacocinética , Receptores CCR8/antagonistas & inibidores , Células Th2/imunologia , Animais , Asma/metabolismo , Asma/fisiopatologia , Fatores Biológicos/administração & dosagem , Líquido da Lavagem Broncoalveolar/química , Quimiocina CCL1/antagonistas & inibidores , Quimiocina CCL1/biossíntese , Quimiocina CCL1/imunologia , Modelos Animais de Doenças , Feminino , Infusões Intravenosas , Pulmão/efeitos dos fármacos , Pulmão/fisiopatologia , Complacência Pulmonar , Macaca fascicularis , Masculino , Receptores CCR8/biossíntese , Receptores CCR8/imunologia , Células Th2/metabolismoRESUMO
The design, synthesis, and structure-activity relationship development of naphthalene-derived human CCR8 antagonists is described. In vitro binding assay results of these investigations are reported, critical interactions of the antagonists with CCR8 are defined, and preliminary physicochemical and pharmacokinetic data for the naphthalene scaffold are presented.
Assuntos
Naftalenos/síntese química , Receptores de Quimiocinas/antagonistas & inibidores , Sulfonamidas/síntese química , Administração Oral , Animais , Disponibilidade Biológica , Transporte Biológico , Cálcio/metabolismo , Linhagem Celular , Cricetinae , Cricetulus , Desenho de Fármacos , Humanos , Naftalenos/farmacocinética , Naftalenos/farmacologia , Ratos , Receptores CCR8 , Solubilidade , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologiaRESUMO
2-Alkyl- and 2,4-dialkyl-3-iodo-1-oxocyclohexan-2,4-carbolactones undergo ammonia-promoted fragmentation reactions to provide butenolides, gamma-butyrolactone, and/or beta,gamma-epoxycyclohexanones. Product distribution is governed by the relative size of the substituents at C-2 and C-4 of the cyclohexanones. Butenolide amide, the major product from the fragmentation, is further converted into their respective piperidinone and pyrrolidine derivatives.
Assuntos
Amônia/química , Cicloexanonas/química , Lactonas/química , Catálise , Ciclização , Indicadores e Reagentes , Lítio/química , Estrutura MolecularRESUMO
2-Alkyl- and 2,4-dialkyl-3-iodo-1-oxocyclohexan-2,4-carbolactones undergo lithium hydroxide- and lithium alkoxide-induced fragmentation reactions to provide butenolides, gamma-hydroxycyclohexenones, and/or gamma-butyrolactones. In general, product distribution is governed by two factors: (1) the nature of nucleophiles and (2) the steric bulkiness of the substituents at C-2 and C-4 of the cyclohexanones. Lithium hydroxide-induced fragmentation provides butenolides and gamma-hydroxycyclohexenones. In contrast, lithium alkoxide-promoted fragmentation results in predominantly 5-substituted gamma-butyrolactones along with a small amount of butenolides in limited cases. Fragmentation products induced by lithium hydroxide are largely influenced by the steric bulkiness of the substituents at C-2 and C-4 of the cyclohexanone ring. The bulky substituents render the exclusive formation of butenolides.
Assuntos
Cicloexanonas/química , Lactonas/química , Catálise , Ciclização , Lítio/química , Estrutura Molecular , EstereoisomerismoRESUMO
The melanocortin 4 receptor (MC4R) plays an important role in body weight regulation and energy homeostasis. Administration of peptidic MC4R antagonists (usually by intracerebro ventricular injection) has been shown in the literature to increase body weight and/or food intake in several rodent models. We report here the identification of a novel nonpeptidic MC4R antagonist and its effects on tumor-induced weight loss in mice following peripheral administration.