Discovery of N-substituted-endo-3-(8-aza-bicyclo[3.2.1]oct-3-yl)-phenol and -phenyl carboxamide series of µ-opioid receptor antagonists.

Gastrointestinal dysfunction as a consequence of the use of opioid analgesics is of significant clinical concern. First generation drugs to treat these opioid-induced side-effects were limited by their negative impact on opioid receptor agonist-induced analgesia. Second generation therapies target a localized, peripherally-restricted, non-CNS penetrant drug distribution of opioid receptor antagonists. Herein we describe the discovery of the N-substituted-endo-3-(8-aza-bicyclo[3.2.1]oct-3-yl)-phenol and -phenyl carboxamide series of µ-opioid receptor antagonists. This report highlights the discovery of the key µ-opioid receptor antagonist pharmacophore and the optimization of in vitro metabolic stability through the application of a phenol bioisostere. The compounds 27a and 31a with the most attractive in vitro profile, formed the basis for the application of Theravance Biopharma's multivalent approach to drug discovery to afford the clinical compound axelopran (TD-1211), targeted for the treatment of opioid-induced constipation.

Multivalent design of long-acting ß(2)-adrenoceptor agonists incorporating biarylamines.

A series of potent ß2-adrenoceptor agonists incorporating a biarylamine secondary binding group was identified. The previously reported milveterol (5), identified by a multivalent approach and containing a typical ß2-agonist primary binding group linked via a phenethylamine linker to a hydrophilic secondary binding group, served as an initiation point. A more hydrophobic set of secondary binding groups was explored, prepared rapidly from a common intermediate by Buchwald-Hartwig amination. TD-5471 (25), a potent and selective full agonist of the human ß2-adrenoceptor, was identified as the most promising agent. It is potent, with slow onset in an in vitro guinea pig trachea model and shows a dose-dependent and long duration of action in an in vivo guinea pig model of bronchoprotection. TD-5471 is structurally differentiated from milveterol and its long duration of action is consistent with a correlation with hydrophobicity observed in other long-acting ß2-agonist discovery programs.

Discovery of TD-4306, a long-acting ß2-agonist for the treatment of asthma and COPD.

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.