ABSTRACT
Several new potent and selective A(2B) adenosine receptor antagonists have been prepared in which the aryl-amide moiety of the lead series, exemplified by 1a, has been replaced by bioisosteric bicyclic moieties. Although the majority of compounds had generally improved microsomal stability as compared to 1a, this was not translated into overall improvements in the pharmacokinetic profiles of a representative set of compounds.
Subject(s)
Adenosine A2 Receptor Antagonists , Amides/chemistry , Anti-Inflammatory Agents/chemistry , Bridged Bicyclo Compounds/chemistry , Animals , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/pharmacokinetics , Bridged Bicyclo Compounds/chemical synthesis , Bridged Bicyclo Compounds/pharmacokinetics , Drug Discovery , Humans , Microsomes, Liver/metabolism , NADP/metabolism , Rats , Receptor, Adenosine A2B/metabolismABSTRACT
The synthesis and structure-activity relationships of piperidinylpyrrolopyridines as potent and selective H(1) antagonists are discussed. It was found that the nature of the acid chain bonded to piperidine was a key feature for maintaining both the duration of action in vivo and lack of sedative properties.
Subject(s)
Histamine H1 Antagonists/chemical synthesis , Pyridines/chemical synthesis , Administration, Oral , Animals , Blood-Brain Barrier , Capillary Permeability , Guinea Pigs , Histamine H1 Antagonists/pharmacokinetics , Histamine H1 Antagonists/pharmacology , Humans , Inhibitory Concentration 50 , Pyridines/pharmacokinetics , Pyridines/pharmacology , Rats , Solubility , Structure-Activity RelationshipABSTRACT
A series of indolylpiperidinyl derivatives were prepared and evaluated for their activity as histamine H(1) antagonists. Structure-activity relationship studies were directed toward improving in vivo activity and pharmacokinetic profile of our first lead (1). Substitution of fluorine in position 6 on the indolyl ring led to higher in vivo activity in the inhibition of histamine-induced cutaneous vascular permeability assay but lower selectivity toward 5HT(2) receptor. Extensive optimization was carried out within this series and a number of histamine H(1) antagonists showing potency and long duration of action in vivo and low brain penetration or cardiotoxic potential were identified. Within this novel series, indolylpiperidines 15, 20, 48,51 and 52 exhibited a long half-life in rat and have been selected for further preclinical evaluation.
