ABSTRACT
Fused aromatics such as naphthalene were identified as highly potent and CNS penetrant M(1) positive allosteric modulators during an SAR study to replace the phenyl B-ring linkage.
Subject(s)
Naphthols/chemistry , Receptor, Muscarinic M1/metabolism , ATP Binding Cassette Transporter, Subfamily B, Member 1/blood , ATP Binding Cassette Transporter, Subfamily B, Member 1/cerebrospinal fluid , Allosteric Regulation/drug effects , Animals , Carboxylic Acids/chemistry , Carboxylic Acids/pharmacology , Humans , Molecular Structure , Naphthols/pharmacology , Quinolones/chemistry , Quinolones/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
A new class of indazole-derived bradykinin B(1) antagonists and their structure-activity relationships (SAR) is reported. A number of compounds were found to have low-nanomolar affinity for the human B(1) receptor and possess acceptable P-gp and pharmacokinetics properties.
Subject(s)
Bradykinin B1 Receptor Antagonists , Indazoles/pharmacology , ATP Binding Cassette Transporter, Subfamily B, Member 1 , Humans , Indazoles/pharmacokinetics , Protein Binding , Structure-Activity RelationshipABSTRACT
Replacement of a phenyl ring with N-linked heterocycles in a series of quinolone carboxylic acid M1 positive allosteric modulators was investigated. In particular, a pyrazole derivative exhibited improvements in potency, free fraction, and CNS exposure.
Subject(s)
Carboxylic Acids/chemical synthesis , Heterocyclic Compounds/chemical synthesis , Pyrazoles/chemical synthesis , Quinolines/chemical synthesis , Allosteric Regulation , Animals , CHO Cells , Carboxylic Acids/chemistry , Carboxylic Acids/pharmacology , Cell Line , Cricetinae , Cricetulus , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Humans , Molecular Structure , Pyrazoles/chemistry , Pyrazoles/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
Incorporation of pyridines and diazines into the biphenyl region of quinolone carboxylic acid derived M(1) positive allosteric modulators was investigated as a means of lowering plasma protein binding to enhance CNS exposure.
Subject(s)
Blood Proteins/chemistry , Pyridines/chemistry , Receptor, Muscarinic M1/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Allosteric Regulation , Animals , Blood Proteins/metabolism , Humans , Protein Binding , Pyridines/chemical synthesis , Pyridines/pharmacology , Rats , Receptor, Muscarinic M1/metabolism , Structure-Activity RelationshipABSTRACT
A series of indole amidines modified at the 2-position of the indole ring were evaluated as inhibitors of Acid-Sensing Ion Channel-3 (ASIC3), a novel target for the treatment of chronic pain.
