RESUMO
Melanin-concentrating hormone (MCH) is a cyclic, nonadecapeptide expressed in the CNS of all vertebrates that regulates feeding behavior and energy homeostasis via interaction with the central melanocortin system. Regulation of this interaction results in modulation of food intake and body weight gain, demonstrating significant therapeutic potential for the treatment of obesity. The MCH-1 receptor (MCH-R1) has been identified as a key target in MCH regulation, as small molecule antagonists of MCH-R1 have demonstrated activity in vivo. Herein, we document our research in a bicyclo[3.1.0]hexyl urea series with particular emphasis on structure-activity relationships and optimization of receptor occupancy, measured both in vitro and via an ex vivo binding assay following an oral dosing regimen. Several compounds have been tested in vivo and exhibit oral efficacy in relevant acute rodent feeding models. In particular, 24u has proven efficacious in chronic rodent models of obesity, showing a statistically significant reduction in food intake and body weight over a 28 day study.
Assuntos
Fármacos Antiobesidade/síntese química , Compostos de Fenilureia/síntese química , Piperazinas/síntese química , Receptores de Somatostatina/antagonistas & inibidores , Ureia/análogos & derivados , Ureia/síntese química , Administração Oral , Animais , Fármacos Antiobesidade/farmacologia , Disponibilidade Biológica , Peso Corporal/efeitos dos fármacos , Encéfalo/metabolismo , Células CHO , Cricetinae , Cricetulus , Ingestão de Alimentos/efeitos dos fármacos , Meia-Vida , Masculino , Obesidade/tratamento farmacológico , Compostos de Fenilureia/farmacologia , Piperazinas/farmacologia , Ensaio Radioligante , Ratos , Receptores de Somatostatina/metabolismo , Relação Estrutura-Atividade , Distribuição Tecidual , Ureia/farmacologiaRESUMO
Herein, we report a small molecule MCH-R1 antagonist which demonstrates oral efficacy in chronic rodent models. Substituted phenyl biaryl urea derivatives were synthesized and evaluated as MCH-R1 antagonists for the treatment of obesity. The structure-activity relationship studies in this series resulted in identification of urea 1 as a potent and selective MCH-R1 antagonist. Compound 1 exhibited oral efficacy in chronic (28 d) rodent models at 3-30 mpk showing significant reduction in food intake and weight gain relative to controls.
Assuntos
Obesidade/tratamento farmacológico , Receptores de Somatostatina/antagonistas & inibidores , Ureia/análogos & derivados , Ureia/síntese química , Administração Oral , Animais , Peso Corporal/efeitos dos fármacos , Cálcio/metabolismo , Células Cultivadas , Doença Crônica , Humanos , Obesidade/metabolismo , Ratos , Receptores de Somatostatina/genética , Relação Estrutura-Atividade , Ureia/farmacologiaRESUMO
We previously reported the discovery of 4-[(Z)-(4-bromophenyl)(ethoxyimino)methyl]-1'-[(2,4-dimethyl-3-pyridinyl)carbonyl]-4'-methyl-1,4'-bipiperidine N-oxide 1 (SCH 351125) as an orally bioavailable human CCR5 antagonist for the treatment of HIV-1 infection. Herein, we describe in detail the discovery of 1 from our initial lead compound as well as the synthesis and SAR studies directed toward optimization of substitution at the phenyl, oxime, and right-hand side amide groups in the oximino-piperidino-piperidine series. Substitutions (4-Br, 4-CF(3), 4-OCF(3), 4-SO(2)Me, and 4-Cl) at the phenyl group are well-tolerated, and small alkyl substitutions (Me, Et, (n)()Pr, (i)()Pr, and cyclopropyl methyl) at the oxime moiety are preferred for CCR5 antagonism. The 2,6-dimethylnicotinamide N-oxide moiety is the optimal choice for the right-hand side. Several compounds in this series, including compound 1, exhibited excellent antiviral activity in vitro. Compound 1, which has a favorable pharmacokinetic profile in rodents and primates, excellent oral bioavailability, and potent antiviral activity against a wide range of primary HIV-1 isolates, is a potentially promising new candidate for treatment of HIV-1 infection.
Assuntos
Fármacos Anti-HIV/síntese química , Antagonistas dos Receptores CCR5 , Óxidos N-Cíclicos/síntese química , Piperidinas/síntese química , Piridinas/síntese química , Administração Oral , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Disponibilidade Biológica , Linhagem Celular , Óxidos N-Cíclicos/química , Óxidos N-Cíclicos/farmacologia , HIV-1/efeitos dos fármacos , HIV-1/isolamento & purificação , Humanos , Técnicas In Vitro , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/virologia , Camundongos , Oximas , Piperidinas/química , Piperidinas/farmacologia , Piridinas/química , Piridinas/farmacologia , Ensaio Radioligante , Ratos , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacosRESUMO
Herein, we report the discovery of an effective strategy to modulate liabilities related to affinity of previously disclosed bicyclohexane MCHR-1 antagonists for the hERG channel. This paper describes one of several strategies incorporated to limit hERG binding via modifications of a terminal aryl group in an otherwise promising bicyclohexyl urea series.
Assuntos
Canais de Potássio Éter-A-Go-Go/metabolismo , Melaninas/química , Receptores de Somatostatina/antagonistas & inibidores , Ureia/farmacologia , Química Farmacêutica , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Cinética , Modelos Químicos , Ligação Proteica , Ureia/químicaRESUMO
Herein, we report the discovery of the potent and selective biaryl diamide derived MCH-R1 receptor antagonist 1, which was identified upon modification of a previously disclosed biaryl urea series. This paper describes one of the strategies incorporated to remove the highly mutagenic biarylaniline present in an otherwise promising biaryl urea series.
Assuntos
Amidas/química , Amidas/farmacologia , Receptores de Somatostatina/antagonistas & inibidores , Amidas/síntese química , Humanos , Relação Estrutura-Atividade , Ureia/químicaRESUMO
The synthesis, SAR and biological evaluation of symmetrical amide analogues of our clinical candidate SCH 351125 are described. A series of potent and orally bioavailable CCR5 antagonists containing symmetrical 2,6-dimethyl isonicotinamides and 2, 6-dimethyl pyrimidines amides were generated with enhanced affinity for the CCR5 receptor.
Assuntos
Amidas/síntese química , Fármacos Anti-HIV/síntese química , Antagonistas dos Receptores CCR5 , Compostos Heterocíclicos com 3 Anéis/síntese química , Piperidinas/síntese química , Amidas/farmacocinética , Amidas/farmacologia , Animais , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/farmacologia , Quimiocina CCL5/antagonistas & inibidores , Óxidos N-Cíclicos , Avaliação Pré-Clínica de Medicamentos , HIV-1/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Concentração Inibidora 50 , Oximas , Piperidinas/farmacocinética , Piperidinas/farmacologia , Piridinas , Ratos , Relação Estrutura-AtividadeRESUMO
The separation and biological evaluation of rotamers as well as interconversion studies on rotamers of our clinical candidate SCH 351125 are described.
Assuntos
Fármacos Anti-HIV/química , Antagonistas dos Receptores CCR5 , Óxidos N-Cíclicos/química , Óxidos N-Cíclicos/farmacologia , Piperidinas , Piridinas/química , Piridinas/farmacologia , Fármacos Anti-HIV/farmacologia , Disponibilidade Biológica , Quimiocina CCL5/antagonistas & inibidores , Cromatografia Líquida de Alta Pressão , HIV/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Isomerismo , Oximas , EstereoisomerismoRESUMO
To study HIV-1 escape from a coreceptor antagonist, the R5 primary isolate CC1/85 was passaged in peripheral blood mononuclear cells with increasing concentrations of the CCR5-specific small molecule inhibitor, AD101. By 19 passages, an escape mutant emerged with a >20,000-fold resistance to AD101. This virus was cross-resistant to a related inhibitor, SCH-C, and partially resistant to RANTES but still sensitive to CCR5-specific mAbs. The resistant phenotype was stable; the mutant virus retained AD101 resistance during nine additional passages of culture in the absence of inhibitor. Replication of the escape mutant in peripheral blood mononuclear cells completely depended on CCR5 expression and did not occur in cells from CCR5-Delta32 homozygous individuals. The escape mutant was unable to use CXCR4 or any other tested coreceptor to enter transfected cells. Acquisition of CXCR4 use is not the dominant in vitro escape pathway for a small molecule CCR5 entry inhibitor. Instead, HIV-1 acquires the ability to use CCR5 despite the inhibitor, first by requiring lower levels of CCR5 for entry and then probably by using the drug-bound form of the receptor.