ABSTRACT
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.
ABSTRACT
A multivalent approach focused on amine-based secondary binding groups was applied to the discovery of long-acting inhaled ß2-agonists. Addition of amine moieties to the neutral secondary binding group of an existing ß2-agonist series was found to provide improved in vivo efficacy, but also led to the formation of biologically active aldehyde metabolites which were viewed as a risk for the development of these compounds. Structural simplification of the scaffold and blocking the site of metabolism to prevent aldehyde formation afforded a potent series of dibasic ß2-agonists with improved duration of action relative to their monobasic analogs. Additional optimization led to the discovery of 29 (TD-4306), a potent and selective ß2-agonist with potential for once-daily dosing.
Subject(s)
Adrenergic beta-2 Receptor Agonists/pharmacology , Asthma/drug therapy , Diphenylamine/analogs & derivatives , Drug Discovery , Pulmonary Disease, Chronic Obstructive/drug therapy , Quinolones/pharmacology , Receptors, Adrenergic, beta-2/metabolism , Adrenergic beta-2 Receptor Agonists/chemical synthesis , Adrenergic beta-2 Receptor Agonists/chemistry , Animals , Asthma/metabolism , Cell Line , Diphenylamine/chemical synthesis , Diphenylamine/chemistry , Diphenylamine/pharmacology , Disease Models, Animal , Dogs , Dose-Response Relationship, Drug , Guinea Pigs , Humans , Molecular Structure , Pulmonary Disease, Chronic Obstructive/metabolism , Quinolones/chemical synthesis , Quinolones/chemistry , Rats , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Benzimidazoles/chemistry , Piperidines/chemistry , Receptors, Serotonin, 5-HT4/chemistry , Serotonin 5-HT4 Receptor Agonists/chemistry , Animals , Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacokinetics , Crystallography, X-Ray , Dogs , Drug Evaluation, Preclinical , Guinea Pigs , Half-Life , Intestinal Mucosa/metabolism , Male , Molecular Conformation , Piperidines/chemical synthesis , Piperidines/pharmacokinetics , Protein Isoforms/antagonists & inhibitors , Protein Isoforms/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Serotonin, 5-HT4/metabolism , Serotonin 5-HT4 Receptor Agonists/chemical synthesis , Serotonin 5-HT4 Receptor Agonists/pharmacokineticsABSTRACT
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.
