RESUMO
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
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.
Assuntos
Desenho de Fármacos , Gastroenteropatias/tratamento farmacológico , Agonistas do Receptor 5-HT4 de Serotonina , Administração Oral , Animais , Sítios de Ligação , Disponibilidade Biológica , Linhagem Celular , Cães , Humanos , Masculino , Movimento/efeitos dos fármacos , Piperazinas/administração & dosagem , Piperazinas/síntese química , Piperazinas/farmacocinética , Piperazinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores 5-HT4 de Serotonina/metabolismo , Especificidade por SubstratoRESUMO
We demonstrate here that covalent dimerization of 5-HT 1 ligands is an effective design strategy to modulate affinity and selectivity of 5-HT 1 ligands. This approach was applied to LY-334370, a selective agonist of 5-HT 1F receptor, to generate structurally well-defined divalent molecules. Radioligand binding assays to three cloned 5-HT 1 receptor subtypes (5-HT 1B, 5-HT 1D, 5-HT 1F) demonstrated that the affinity of a series of homologous dimers varied significantly upon exploration of three structural variables (linker length, attachment position, functionality). In particular, the series of C 3-to-C 3 linked dimers derived from a monomer ( 3) showed high binding affinity to 5-HT 1D (for example, K i approximately 0.3 nM for dimer 8) but did not bind to 5-HT 1F ( K i > 0.01 mM), providing >10000-fold subtype selectivity. Results from a functional assay (rabbit saphenous vein contraction) demonstrate that certain dimers are 5-HT 1 receptor agonists.
Assuntos
Benzamidas/síntese química , Indóis/síntese química , Receptor 5-HT1D de Serotonina/metabolismo , Receptores de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/síntese química , Animais , Benzamidas/química , Benzamidas/farmacologia , Células CHO , Cricetinae , Cricetulus , Dimerização , Técnicas In Vitro , Indóis/química , Indóis/farmacologia , Ligantes , Contração Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/fisiologia , Coelhos , Ensaio Radioligante , Receptor 5-HT1B de Serotonina/metabolismo , Veia Safena/efeitos dos fármacos , Veia Safena/fisiologia , Agonistas do Receptor 5-HT1 de Serotonina , Agonistas do Receptor de Serotonina/química , Agonistas do Receptor de Serotonina/farmacologia , Relação Estrutura-Atividade , Receptor 5-HT1F de SerotoninaRESUMO
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.