ABSTRACT
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.
Subject(s)
Azabicyclo Compounds/pharmacology , Azabicyclo Compounds/pharmacokinetics , Constipation/drug therapy , Drug Discovery , Receptors, Serotonin, 5-HT4/metabolism , Serotonin 5-HT4 Receptor Agonists/pharmacology , Serotonin 5-HT4 Receptor Agonists/pharmacokinetics , Animals , Azabicyclo Compounds/administration & dosage , Azabicyclo Compounds/therapeutic use , Chronic Disease , Guinea Pigs , Humans , Molecular Structure , Rats , Serotonin 5-HT4 Receptor Agonists/chemistry , Serotonin 5-HT4 Receptor Agonists/therapeutic use , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Drug Design , Gastrointestinal Diseases/drug therapy , Serotonin 5-HT4 Receptor Agonists , Administration, Oral , Animals , Binding Sites , Biological Availability , Cell Line , Dogs , Humans , Male , Movement/drug effects , Piperazines/administration & dosage , Piperazines/chemical synthesis , Piperazines/pharmacokinetics , Piperazines/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Serotonin, 5-HT4/metabolism , Substrate SpecificityABSTRACT
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.
Subject(s)
Benzamides/chemical synthesis , Indoles/chemical synthesis , Receptor, Serotonin, 5-HT1D/metabolism , Receptors, Serotonin/metabolism , Serotonin Receptor Agonists/chemical synthesis , Animals , Benzamides/chemistry , Benzamides/pharmacology , CHO Cells , Cricetinae , Cricetulus , Dimerization , In Vitro Techniques , Indoles/chemistry , Indoles/pharmacology , Ligands , Muscle Contraction/drug effects , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/physiology , Rabbits , Radioligand Assay , Receptor, Serotonin, 5-HT1B/metabolism , Saphenous Vein/drug effects , Saphenous Vein/physiology , Serotonin 5-HT1 Receptor Agonists , Serotonin Receptor Agonists/chemistry , Serotonin Receptor Agonists/pharmacology , Structure-Activity Relationship , Receptor, Serotonin, 5-HT1FABSTRACT
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.
