Discovery of Novel Potent Muscarinic M3 Receptor Antagonists with Proper Plasma Stability by Structural Recombination of Marketed M3 Antagonists. (25th July 2017)

• Record Type: Journal Article
• Authors: Xiang, Zuojuan; Liu, Jun; Sun, Hongbin; Wen, Xiaoan
• Is Part Of: ChemMedChem. Volume 12:Number 15(2017)
• Page Start: 1173
• Page End: 1182
• Publication Date: 2017-07-25
• Subjects: ammonium salts -- antagonists -- nitrogen heterocycles -- stability -- structure–activity relationships; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201700189
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: The marketed long‐acting M3 antagonists for treatment of chronic obstructive pulmonary disease have inappropriate plasma stability (either overstable or excessively unstable), which causes substantial systemic exposure or poor patient compliance. To discover novel M3 antagonists with proper plasma stability, we synthesized and biologically evaluated a series of chiral quaternary ammonium salts of pyrrolidinol esters, which were designed by structural recombination of the marketed M3 antagonists. As a result, two novel potent M3 antagonists, ( R / S )‐3‐[2‐hydroxy‐2, 2‐di(thiophen‐2‐yl)acetoxy]‐1, 1‐dimethylpyrrolidinium bromides (1 a : K i =0.16 nm, IC50 =0.38 nm, t 1/2 =9.34 min;1 b : K i =0.32 nm, IC50 =1.01 nm, t 1/2 =19.2 min) with proper plasma stability were identified, which (particularly1 a ) hold great promise as clinical drug candidates to overcome the drawbacks caused by the inappropriate stability of the currently marketed M3 antagonists. In addition, structure–activity relationship studies revealed that the R configuration of the pyrrolidinyl C3 atom was clearly better than the S configuration. Abstract : Steady as she goes : Structural recombination of the marketed muscarinic M3 receptor antagonists aclidinium bromide and glycopyrronium bromide, which have inappropriate plasma stability, led to the discovery of novel potent M3 receptor antagonists1 a and1 b, which have proper plasma stability. These antagonists hold great promise as clinical drug candidates to overcome the drawbacks caused by the unsuitable stability of currently marketed M3 antagonists.