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Chemical development of astemizole‐like compounds
Author(s) -
Janssens Frans,
Janssen Marcel A. C.,
Awouters Frans,
Niemegeers Carlos J. E.,
Vanden Bussche Gabriel
Publication year - 1986
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.430080105
Subject(s) - astemizole , chemistry , pharmacology , histamine , piperidine , potency , benzimidazole , stereochemistry , in vitro , medicine , biochemistry , organic chemistry
Newly synthesized diphenylbutylpiperidine derivatives were devoid of neuroleptic activity but were moderately active histamine antagonists in vitro. Their structural relation to classical antihistamines was not evident, but the requirement of a piperidino‐2‐aminobenzimidazole core was confirmed by the synthesis of R 39848, which was more potent. About 500 new compounds related to R 39848 were synthesized by varying in particular the alkyl and aralkyl groups implanted on the piperidine, benzimidazole, and bridging amine nitrogen. Potency, oral activity, and long duration of action in the compound 48/80 lethality test in rats prompted the selection of R 43512 (astemizole) for detailed pharmacological studies. Antiallergic specificity and lack of central effects were the conclusions of all studies, and the higher clinical effectiveness of astemizole was in agreement with a dosage that is not limited by central or other side effects. More extensive chemical modifications of the astemizole molecule were explored, and it is possible that some recent compounds may either have an increased antiallergic effectiveness (R 57959) or be useful in other indications because of a different profile of peripheral actions.