ABSTRACT
We designed and synthesized novel N-substituted 7-azaindoline derivatives as selective M1 and M4 muscarinic acetylcholine receptors (mAChRs) agonists. Hybridization of compound 2 with the HTS hit compound 5 followed by optimization of the N-substituents of 7-azaindoline led to identification of compound 1, which showed highly selective M1 and M4 mAChRs agonistic activity, weak human ether-a-go-go related gene inhibition, and good bioavailability in multiple animal species.
Subject(s)
Drug Discovery , Indoles/pharmacology , Piperidines/pharmacology , Receptor, Muscarinic M1/agonists , Receptor, Muscarinic M4/agonists , Administration, Oral , Animals , Dose-Response Relationship, Drug , Haplorhini , Humans , Indoles/administration & dosage , Indoles/chemistry , Molecular Structure , Piperidines/administration & dosage , Piperidines/chemistry , Rats , Structure-Activity RelationshipABSTRACT
We designed and synthesized N-substituted 8-azatetrahydroquinolone derivatives as selective M1 and M4 muscarinic acetylcholine receptors agonists. Optimization of selected derivatives led to the discovery of compound 7 as a highly potent M1 and M4 agonist with weak hERG inhibition. Oral administration of compound 7 improved psychosis-like behavior in rats.
Subject(s)
Antipsychotic Agents/pharmacology , Hydroquinones/chemical synthesis , Hydroquinones/pharmacology , Receptor, Muscarinic M1/agonists , Receptor, Muscarinic M4/agonists , Administration, Oral , Animals , Antipsychotic Agents/chemical synthesis , Antipsychotic Agents/chemistry , Aza Compounds/chemical synthesis , Aza Compounds/chemistry , Aza Compounds/pharmacology , Behavior, Animal/drug effects , Hydroquinones/chemistry , Molecular Structure , Rats , Structure-Activity RelationshipABSTRACT
A series of peptide-based transition-state human neutrophil elastase (HNE) inhibitors with N-terminal acidic moieties were synthesized and their inhibitory activity against HNE was evaluated both in vitro and in vivo. Our results show that compounds containing cyclic amide bridged acidic moieties at the N-terminal have not only improved water solubility but also high in vivo potency. Among these compounds, AE-3763 showed remarkable efficacy in hamster models of elastase-induced lung hemorrhage and lipopolysaccharide (LPS)-induced lung injury as well as in a mouse model of LPS/galactosamine-induced acute multiple organ dysfunctions. The water solubility of AE-3763 (>1000 mg/ml in H(2)O) was also far superior to that of any of the other compounds synthesized. Thus, it is believed that AE-3763 would be useful for treatment of HNE-associated respiratory disorders, such as acute respiratory distress syndrome (ARDS), acute lung injury (ALI), and acute exacerbation of chronic obstructive pulmonary disease (COPD).
Subject(s)
Acute Lung Injury/drug therapy , Dipeptides/chemistry , Leukocyte Elastase/antagonists & inhibitors , Peptides/chemistry , Proteinase Inhibitory Proteins, Secretory/chemistry , Animals , Cricetinae , Dipeptides/chemical synthesis , Dipeptides/pharmacology , Disease Models, Animal , Galactosamine/toxicity , Humans , Leukocyte Elastase/metabolism , Lipopolysaccharides/toxicity , Mice , Proteinase Inhibitory Proteins, Secretory/chemical synthesis , Proteinase Inhibitory Proteins, Secretory/pharmacology , SolubilityABSTRACT
In our search for a new agent, human neutrophil elastase (HNE) inhibitor, for the treatment of acute respiratory failure, we rationally designed and synthesized a series of peptide-based carboxylic acid-containing transition-state inhibitors. The presence of valyl moiety is found to be essential for potent in vitro inhibitory activity and also prevention of an undesirable toxicity. Of these, compound 9m has the most potent in vivo effect on HNE-induced lung hemorrhage in hamsters.
