ABSTRACT
Tyrosine ureas had been identified as potent muscarinic receptor antagonists with promising in vivo activity. Controlling the stereochemistry of the chiral quaternary ammonium center had proved to be a serious issue for this series, however. Herein we describe the preparation and SAR of tyrosine urea antagonists containing achiral quaternary ammonium centers. The most successful such moiety was the 2-methylimidazo[2,1-b][1,3]thiazol-7-ium group which yielded highly potent antagonists with long duration of action in an inhaled animal model of bronchoconstriction.
Subject(s)
Muscarinic Antagonists/chemistry , Quaternary Ammonium Compounds/chemistry , Receptors, Muscarinic/chemistry , Tyrosine/chemistry , Urea/analogs & derivatives , Animals , Bronchi/drug effects , Mice , Muscarinic Antagonists/chemical synthesis , Muscarinic Antagonists/pharmacology , Receptors, Muscarinic/metabolism , Structure-Activity Relationship , Urea/chemical synthesis , Urea/pharmacologyABSTRACT
A novel series of N-substituted tropane derivatives was characterized as potent muscarinic acetylcholine receptor antagonists (mAChRs). Kinetic washout studies showed that the N-endosubstituted analog 24 displayed much slower reversibility at mAChRs than the methyl-substituted parent molecule darotropium. In addition, it was shown that this characteristic appeared to translate into enhanced which duration of action in a mouse model of bronchonstriction.
Subject(s)
Muscarinic Antagonists/chemical synthesis , Tropanes/chemical synthesis , Animals , Bronchial Diseases/drug therapy , Drug Design , Mice , Muscarinic Antagonists/pharmacology , Receptors, Muscarinic/drug effects , Structure-Activity Relationship , Tropanes/pharmacologyABSTRACT
SAR exploration of multiple regions of a tyrosine urea template led to the identification of very potent muscarinic acetylcholine receptor antagonists such as 10b with good subtype selectivity for M(3) over M(1). The structure-activity relationships (SAR) and optimization of the tyrosine urea series are described.
Subject(s)
Chemistry, Pharmaceutical/methods , Muscarinic Antagonists/chemical synthesis , Receptors, Muscarinic/chemistry , Tyrosine/chemistry , Urea/chemistry , Asthma/drug therapy , Drug Design , Humans , Inhibitory Concentration 50 , Models, Chemical , Molecular Structure , Muscarinic Antagonists/pharmacology , Salts/chemistry , Structure-Activity RelationshipABSTRACT
High throughput screening and subsequent optimization led to the discovery of novel quaternary ammonium salts as highly potent muscarinic acetylcholine receptor antagonists with excellent selectivity. Compounds 8a, 13a, and 13b showed excellent inhibitory activity and long duration of action in bronchoconstriction in vivo models in two species via intranasal or intratracheal administration. The novel inhaled muscarinic receptor antagonists are potentially useful therapeutic agents for the treatment of chronic obstructive pulmonary disease and other bronchoconstriction disorders.
Subject(s)
Muscarinic Antagonists/pharmacology , Phenylurea Compounds/pharmacology , Quaternary Ammonium Compounds/pharmacology , Tyrosine/analogs & derivatives , Animals , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Bronchoconstriction/drug effects , Drug Evaluation, Preclinical/methods , Guinea Pigs , Mice , Rats , Tyrosine/pharmacologyABSTRACT
N,N'-diarylsquaramides were prepared and evaluated as antagonists of CXCR2. The compounds were found to be potent and selective antagonists of CXCR2. Significant differences in SAR was observed relative to the previously described N,N'-diarylurea series. As was the case in the N,N'-diarylurea series, placing sulfonamide substituent adjacent to the acidic phenol significantly reduced the clearance in rat pharmacokinetic studies.
