Synthesis and antibronchospastic activity of 8-alkoxy- and 8-(alkylamino)imidazo[1,2-a]pyrazines.
Theophylline still occupies a dominant place in asthma therapy. Unfortunately its adverse central nervous system (CNS) stimulant effects can dramatically limit its use, and adjustments in the dosage are often needed. We have synthesized a new series of imidazo[1,2-alpha]pyrazine derivatives which are much more potent bronchodilators than theophylline in vivo and do not exhibit the CNS stimulatory profile. In vitro studies on isolated rat uterus and guinea pig trachea confirm the high potentialities of these derivatives. 6-Bromo-8-(methylamino)imidazo[1,2-alpha]-pyrazine-3-carbonitrile (23) is identified as the most potent compound of the series. As in the case of theophylline, phosphodiesterase inhibition appears unlikely to be the unique mechanism of action of this series of heterocycles.
Bonnet
P A
PA
URA CNRS 1111, Laboratoire de Chimie Organique Pharmaceutique, Faculté de Pharmacie, Montpellier, France.
Michel
A
A
Laurent
F
F
Sablayrolles
C
C
Rechencq
E
E
Mani
J C
JC
Boucard
M
M
Chapat
J P
JP
D000818:Animals; D001993:Bronchodilator Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011719:Pyrazines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013806:Theophylline / Q000494:pharmacology
D001993:Bronchodilator Agents; D007093:Imidazoles; D010726:Phosphodiesterase Inhibitors; D011719:Pyrazines; D013806:Theophylline