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
Lowering of intra-ocular pressure is the primary pharmacologic approach for the treatment of glaucoma and a number of distinct mechanisms of action have been clinically validated. Targeting of multiple mechanisms in combination therapies has proven effective both clinically and commercially although potential improvements with regards to efficacy, tolerability and dosing frequency remain. Application of Theravance's multivalent approach to drug discovery towards linked dual-pharmacology prostaglandin F receptor (FP) agonist/carbonic anhydrase (CA)-II inhibitor compounds is described. Compound 29 exhibits weak potency (pEC(50)=5.7, IA>1.0) as an FP agonist with high binding affinity (pK(i)=8.1) to the CA-II enzyme, and has comparable corneal permeability to the CA-II inhibitor dorzolamide.
Assuntos
Inibidores da Anidrase Carbônica/farmacologia , Glaucoma/tratamento farmacológico , Prostaglandinas F Sintéticas/farmacologia , Receptores de Prostaglandina/agonistas , Inibidores da Anidrase Carbônica/química , Descoberta de Drogas , Humanos , Modelos Moleculares , Prostaglandinas F Sintéticas/química , Receptores de Prostaglandina/químicaRESUMO
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
Dual inhibition of angiotensin-converting enzyme (ACE) and neprilysin (NEP) by drugs such as omapatrilat produces superior antihypertensive efficacy relative to ACE inhibitors but is associated with a higher risk of life-threatening angioedema due to bradykinin elevations. We hypothesized that dual AT1 (angiotensin II type 1 receptor) blockade and NEP inhibition with a single molecule would produce similar antihypertensive efficacy to omapatrilat without the risk of angioedema since ACE (the rate limiting enzyme in bradykinin metabolism) would remain uninhibited. Merging the structures of losartan (an AT1 antagonist) and thiorphan (a NEP inhibitor) led to the discovery of a novel series of orally active, dual AT1 antagonist/NEP inhibitors (ARNIs) exemplified by compound 35 (TD-0212). In models of renin-dependent and -independent hypertension, 35 produced blood pressure reductions similar to omapatrilat and combinations of AT1 receptor antagonists and NEP inhibitors. Upper airway angioedema risk was assessed in a rat tracheal plasma extravasation (TPE) model. Unlike omapatrilat, 35 did not increase TPE at antihypertensive doses. Compound 35 therefore provides the enhanced activity of dual AT1/NEP inhibition with a potentially lower risk of angioedema relative to dual ACE/NEP inhibition.
RESUMO
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
There is a clear and urgent need for novel antibacterial agents that can address the concerns of growing resistance. This article details recent patent activity within the antibiotic field based on the emerging strategy of a multivalent approach to drug discovery. A range of heterodimer antibiotics are discussed, which consist of two antibacterial chemical classes covalently linked to afford compounds with the potential to engage multiple mechanisms of action. The possible benefits of such compounds include activity against drug-resistant bacteria, enhanced efficacy and duration, an expanded spectrum of activity and reduced potential for generating bacterial resistance. This exciting approach towards novel heterodimer antibiotics holds significant promise, but must overcome a range of challenges before yielding a successful medicine. Progress to date is encouraging and has resulted in three compounds entering clinical trials.
Assuntos
Antibacterianos/química , Antibacterianos/uso terapêutico , Infecções Bacterianas/tratamento farmacológico , Patentes como Assunto , Antibacterianos/farmacologia , Ensaios Clínicos como Assunto , Dimerização , Farmacorresistência Bacteriana/efeitos dos fármacos , Estrutura MolecularRESUMO
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.