M3 muscarinic acetylcholine receptor antagonists : SAR and optimization of bi-aryl amines

• Published in: Bioorganic & medicinal chemistry letters Vol. 19; no. 6; pp. 1686 - 1690
• Main Authors: BUDZIK, Brian, YONGHUI WANG, SARAU, Henry M, MORROW, Dwight M, MOORE, Michael L, RIVERO, Ralph A, PALOVICH, Michael, SALMON, Michael, BELMONTE, Kristen E, LAINE, Dramane I, JIAN JIN, DONGCHUAN SHI, FENG WANG, HAIBO XIE, ZEHONG WAN, CHONGYE ZHU, FOLEY, James J, NUTHULAGANTI, Parvathi, KALLAL, Lorena A
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier 15-03-2009
• Subjects: Amides - chemistry; Amines - chemical synthesis; Amines - pharmacology; Asthma - drug therapy; Biological and medical sciences; Chemistry, Pharmaceutical - methods; Cholinergic system; Drug Design; Electrons; Humans; Inhibitory Concentration 50; Kinetics; Medical sciences; Models, Chemical; Molecular Structure; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Pulmonary Disease, Chronic Obstructive - drug therapy; Receptor, Muscarinic M3 - antagonists & inhibitors; Receptor, Muscarinic M3 - chemistry; Respiratory system; Structure-Activity Relationship; SAR; Selectivity; Antagonists; Optimization; M3 mAChR; Cholinergic receptor; Structure activity relation; Piperidine derivatives; Bronchus disease; Chronic obstructive pulmonary disease; Obstructive pulmonary disease; Antagonist; Arylamine; M3 Muscarinic receptor; Lung disease; Sub-type selectivity; Respiratory disease; Bi-aryl amines; Asthma; Muscarinic acetylcholine receptor; Biphenyl derivatives; Carboxamide; Benzamide derivatives; Piperazine derivatives; Fluorine Organic compounds; COPD
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.01.098

Exploration of multiple regions of a bi-aryl amine template led to the identification of highly potent M(3) muscarinic acetylcholine receptor antagonists such as 14 (pA(2)=11.0) possessing good sub-type selectivity for M(3) over M(2). The structure-activity relationships (SAR) and optimization of the bi-aryl amine series are described.