ABSTRACT
We describe here the synthesis of [(14)C]-2-(3-chlorophenyloxy)-3-[3-(3-hydroxy)pyridin-4-yl propoxy]pyridine (1), a phosphodiesterase 4 inhibitor. [(14)C]-Labeled 1 was prepared in three steps from [(14)C]-2-bromopyridin-3-ol in an overall yield of 32%. Preparation of [(14)C]-labeled 2 and 3, two metabolites of 1, is also described.
Subject(s)
Phosphodiesterase 4 Inhibitors/chemical synthesis , Pyridines/chemical synthesis , Radiopharmaceuticals/chemical synthesis , Carbon Radioisotopes/chemistry , Pyridines/chemistryABSTRACT
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.