RESUMO
The synthesis of a range of novel amine-containing structures and their primary potency as inhibitors of HIV-1 fusion via blocking of the CCR5 receptor is described. The development of the medicinal chemistry strategy and SAR's which led to the identification of the piperidine amide compounds 33 and 36 as excellent leads for further evaluation is described, along with key physicochemical data which highlighted their lead potential.
Assuntos
Amidas/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Antagonistas dos Receptores CCR5 , Piperidinas/síntese química , Piperidinas/farmacologia , Fármacos Anti-HIV/química , Técnicas de Química Combinatória , Desenho de Fármacos , Descoberta de Drogas , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , HIV-1/efeitos dos fármacos , Humanos , Microssomos Hepáticos/efeitos dos fármacos , Estrutura Molecular , Piperidinas/química , Relação Estrutura-AtividadeRESUMO
Female sexual arousal disorder (FSAD) is a highly prevalent sexual disorder affecting up to 40% of women. We describe herein our efforts to identify a selective neutral endopeptidase (NEP) inhibitor as a potential treatment for FSAD. The rationale for this approach, together with a description of the medicinal chemistry strategy, lead compounds, and SAR investigations are detailed. In particular, the strategy of starting with the clinically precedented selective NEP inhibitor, Candoxatrilat, and targeting low molecular weight and relatively polar mono-carboxylic acids is described. This led ultimately to the prototype development candidate R-13, for which detailed pharmacology and pharmacokinetic parameters are presented.(1)
Assuntos
Ácidos Carbocíclicos/síntese química , Amidas/síntese química , Neprilisina/antagonistas & inibidores , Ácidos Pentanoicos/síntese química , Disfunções Sexuais Psicogênicas/tratamento farmacológico , Tiadiazóis/síntese química , Ácidos Carbocíclicos/farmacocinética , Ácidos Carbocíclicos/farmacologia , Amidas/farmacocinética , Amidas/farmacologia , Animais , Células CHO , Clitóris/irrigação sanguínea , Clitóris/efeitos dos fármacos , Cricetinae , Cricetulus , Cães , Feminino , Humanos , Masculino , Ácidos Pentanoicos/farmacocinética , Ácidos Pentanoicos/farmacologia , Piridinas/síntese química , Piridinas/farmacocinética , Piridinas/farmacologia , Coelhos , Ratos , Proteínas Recombinantes/antagonistas & inibidores , Fluxo Sanguíneo Regional/efeitos dos fármacos , Especificidade da Espécie , Estereoisomerismo , Relação Estrutura-Atividade , Tiadiazóis/farmacocinética , Tiadiazóis/farmacologia , Vagina/irrigação sanguínea , Vagina/efeitos dos fármacosRESUMO
Preventing entry of HIV into human host cells has emerged as an attractive approach to controlling viral replication. Maraviroc 1 is an approved antagonist of the human CCR5 receptor which prevents the entry of HIV. Herein, we report the design and discovery of a series of imidazopiperidine CCR5 antagonists which retain the attractive antiviral profile and window over hERG activity of maraviroc 1, combined with improved absorption profiles in rat and dog. Furthermore, this series of compounds has been shown to retain activity against a laboratory generated maraviroc-resistant HIV-1 strain, which indicates an alternative resistance profile to that of maraviroc 1. Compound 41f (PF-232798) was selected as a clinical candidate from the imidazopiperidine series and is currently in phase II clinical trials.
Assuntos
Fármacos Anti-HIV/síntese química , Compostos Azabicíclicos/síntese química , Antagonistas dos Receptores CCR5 , HIV-1/efeitos dos fármacos , Imidazóis/síntese química , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Compostos Azabicíclicos/química , Compostos Azabicíclicos/farmacologia , Linhagem Celular , Cricetinae , Cicloexanos/farmacologia , Cães , Farmacorresistência Viral , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/metabolismo , HIV-1/isolamento & purificação , Humanos , Imidazóis/química , Imidazóis/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/virologia , Maraviroc , Modelos Moleculares , Ligação Proteica , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Triazóis/farmacologia , TropanosRESUMO
A series of substituted glutaramides were synthesised using Candoxatrilat 1 as a lead and evaluated for potency against neutral endopeptidase (NEP) as a potential treatment for female sexual arousal disorder (FSAD). In this paper, we describe studies in which we were able to increase NEP activity substantially over the levels reported for previous compounds from this programme by appropriate substitution in both the P(1)(') and P(2)(') regions. Optimisation led to the 4-chlorophenpropylamide S-30 which was selected as a candidate for further study.
Assuntos
Ácidos Cicloexanocarboxílicos/química , Ácidos Cicloexanocarboxílicos/síntese química , Neprilisina/antagonistas & inibidores , Inibidores de Proteases/química , Inibidores de Proteases/síntese química , Disfunções Sexuais Psicogênicas/tratamento farmacológico , Animais , Ácidos Cicloexanocarboxílicos/farmacocinética , Cães , Feminino , Humanos , Concentração de Íons de Hidrogênio , Masculino , Estrutura Molecular , Inibidores de Proteases/farmacocinética , Coelhos , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Especificidade por Substrato , SuínosRESUMO
A series of small molecule glutaramides were synthesized and evaluated for potency against canine and human neutral endopeptidase using target criteria of molecular weight <400 and log P between 2 and 4.5 to maximize the likelihood of achieving good oral absorption. The structure-activity relationship (SAR) investigations described in this paper led to the identification of an ethyl 1,3,4-thiadiazole glutaramide which demonstrated good neutral endopeptidase potency, selectivity and excellent oral absorption in the rat.