RESUMO
The discovery of a series of 5-HT4 receptor agonists based on a novel 2-alkylbenzimidazole aromatic core is described. Optimization of the 2-substituent of the benzimidazole ring led to a series of agonists with subnanomolar binding affinity and moderate-to-high intrinsic activity relative to that of 5-HT. Consistent with our previously described multivalent design approach to this target, subsequent optimization of the linker and secondary binding group regions of the series afforded compound 18 (TD-8954), a potent and selective 5-HT4 receptor agonist in vitro with demonstrated prokinetic activity in multiple species.
Assuntos
Benzimidazóis/química , Piperidinas/química , Receptores 5-HT4 de Serotonina/química , Agonistas do Receptor 5-HT4 de Serotonina/química , Animais , Benzimidazóis/síntese química , Benzimidazóis/farmacocinética , Cristalografia por Raios X , Cães , Avaliação Pré-Clínica de Medicamentos , Cobaias , Meia-Vida , Mucosa Intestinal/metabolismo , Masculino , Conformação Molecular , Piperidinas/síntese química , Piperidinas/farmacocinética , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores 5-HT4 de Serotonina/metabolismo , Agonistas do Receptor 5-HT4 de Serotonina/síntese química , Agonistas do Receptor 5-HT4 de Serotonina/farmacocinéticaRESUMO
Utilization of Theravance's multivalent approach to drug discovery towards 5-HT(4) receptor agonists with a focus on identification of neutral (non-charged at physiological pH) secondary binding groups is described. Optimization of a quinolone-tropane primary binding group with a chiral 2-propanol linker to a range of neutral secondary binding group motifs, for binding affinity and functional potency at the 5-HT(4) receptor, selectivity over the 5-HT(3) receptor, oral pharmacokinetics, and in vivo efficacy in models of GI motility, afforded velusetrag (TD-5108). Velusetrag has achieved proof-of-concept in patients with chronic idiopathic constipation.
Assuntos
Compostos Azabicíclicos/farmacologia , Compostos Azabicíclicos/farmacocinética , Constipação Intestinal/tratamento farmacológico , Descoberta de Drogas , Receptores 5-HT4 de Serotonina/metabolismo , Agonistas do Receptor 5-HT4 de Serotonina/farmacologia , Agonistas do Receptor 5-HT4 de Serotonina/farmacocinética , Animais , Compostos Azabicíclicos/administração & dosagem , Compostos Azabicíclicos/uso terapêutico , Doença Crônica , Cobaias , Humanos , Estrutura Molecular , Ratos , Agonistas do Receptor 5-HT4 de Serotonina/química , Agonistas do Receptor 5-HT4 de Serotonina/uso terapêutico , Relação Estrutura-AtividadeRESUMO
Further application of our multivalent approach to drug discovery directed to 5-HT(4) receptor agonists is described. Optimization of the linker and secondary binding amine in the indazole-tropane primary binding group series, for binding affinity and functional potency at the 5-HT(4) receptor, selectivity over the 5-HT(3) receptor, oral pharmacokinetics, and in vivo efficacy in models of GI motility, resulted in the identification of clinical compound TD-2749.
Assuntos
Compostos Heterocíclicos/química , Piperazinas/química , Agonistas do Receptor 5-HT4 de Serotonina/química , Administração Oral , Animais , Linhagem Celular , Descoberta de Drogas , Compostos Heterocíclicos/administração & dosagem , Compostos Heterocíclicos/farmacocinética , Humanos , Masculino , Estrutura Molecular , Especificidade de Órgãos , Piperazinas/administração & dosagem , Piperazinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Agonistas do Receptor 5-HT4 de Serotonina/administração & dosagem , Agonistas do Receptor 5-HT4 de Serotonina/farmacocinética , Relação Estrutura-AtividadeRESUMO
Further investigations towards novel glycopeptide/beta-lactam heterodimers are reported. Employing a multivalent approach to drug discovery, vancomycin and cephalosporin synthons, 4, 2, 5 and 10, 18, 25 respectively, were chemically linked to yield heterodimer antibiotics. These novel compounds were designed to inhibit Gram-positive bacterial cell wall biosynthesis by simultaneously targeting the principal cellular targets of both glycopeptides and beta-lactams. The positional attachment of both the vancomycin and the cephalosporin central cores has been explored and the SAR is reported. This novel class of bifunctional antibiotics 28-36 all displayed remarkable potency against a wide range of Gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA). A subset of compounds, 29, 31 and 35 demonstrated excellent bactericidal activity against MRSA (ATCC 33591) and 31 and 35 also exhibited superb in vivo efficacy in a mouse model of MRSA infection. As a result of this work compound 35 was selected as a clinical candidate, TD-1792.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Cefalosporinas/síntese química , Cefalosporinas/farmacologia , Descoberta de Drogas/métodos , Glicopeptídeos/síntese química , Glicopeptídeos/farmacologia , beta-Lactamas/síntese química , beta-Lactamas/farmacologia , Animais , Antibacterianos/química , Cefalosporinas/química , Dimerização , Desenho de Fármacos , Feminino , Glicopeptídeos/química , Bactérias Gram-Positivas/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , beta-Lactamas/químicaRESUMO
Novel derivatives of N-decylaminoethylvancomycin (2), containing appended hydrophilic groups were synthesized and their antibacterial activity and ADME properties were evaluated. The compounds were prepared by reacting amines with the C-terminus (C-) of 2 using PyBOP mediated amide formation, or with the resorcinol-like (R-) position of 2 using a Mannich aminomethylation reaction. These analogs retained the antibacterial activity of 2 against methicillin-resistant staphylococci and vancomycin-resistant enterococci. Compounds with a negatively charged auxiliary group also exhibited improved ADME properties relative to 2. In particular, R-phosphonomethylaminomethyl derivative 21 displayed good in vitro antibacterial activity, high urinary recovery and low distribution to liver and kidney tissues. Based on these results, 21 was advanced into development as TD-6424, and is currently in human clinical trials. The generic name telavancin has recently been approved for compound 21.
Assuntos
Aminoglicosídeos/farmacocinética , Antibacterianos/farmacologia , Vancomicina/análogos & derivados , Vancomicina/farmacocinética , Aminoglicosídeos/química , Animais , Fenômenos Químicos , Físico-Química , Cromatografia Líquida de Alta Pressão , Feminino , Bactérias Gram-Positivas/efeitos dos fármacos , Indicadores e Reagentes , Injeções Intravenosas , Lipoglicopeptídeos , Testes de Sensibilidade Microbiana , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas por Ionização por Electrospray , Espectrofotometria Ultravioleta , Teicoplanina/farmacologia , Distribuição TecidualRESUMO
5-HT(4) receptor agonists such as tegaserod have demonstrated efficacy in the treatment of constipation predominant irritable bowel syndrome (IBS-C), a highly prevalent disorder characterized by chronic constipation and impairment of intestinal propulsion, abdominal bloating, and pain. The 5-HT(4) receptor binding site can accommodate functionally and sterically diverse groups attached to the amine nitrogen atom of common ligands, occupying what may be termed a "secondary" binding site. Using a multivalent approach to lead discovery, we have investigated how varying the position and nature of the secondary binding group can be used as a strategy to achieve the desired 5-HT(4) agonist pharmacological profile. During this study, we discovered the ability of amine-based secondary binding groups to impart exceptional gains in the binding affinity, selectivity, and functional potency of 5-HT(4) agonists. Optimization of the leads generated by this approach afforded compound 26, a selective, orally efficacious 5-HT(4) agonist for the potential treatment of gastrointestinal motility-related disorders.