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Pyrido[2,1-b]quinazolinecarboxamide derivatives as platelet activating factor antagonists
J W Tilley1, B Burghardt, C Burghardt
1Department of Pharmacology and Chemotherapy, Hoffmann-La Roche Inc., Nutley, New Jersey 07110.
Journal of Medicinal Chemistry
|February 1, 1988
Summary
Researchers developed novel pyrido[2,1-b]quinazoline-8-carboxamides as potent platelet activating factor (PAF) antagonists. The (R)-enantiomer showed enhanced potency and stability, representing a new class of orally active PAF antagonists.
Area of Science:
- Medicinal Chemistry
- Pharmacology
Background:
- Platelet activating factor (PAF) plays a role in inflammatory and allergic responses.
- Pyrido[2,1-b]quinazolines were explored as potential inhibitors of PAF receptor binding.
Purpose of the Study:
- To synthesize and evaluate N-[(heteroaryl)alkyl]pyrido[2,1-b]quinazolines for PAF receptor antagonism.
- To investigate structure-activity relationships, including the impact of isosteric replacements and stereochemistry.
Main Methods:
- Synthesis of pyrido[2,1-b]quinazoline derivatives.
- In vitro PAF receptor binding assays using radiolabeled PAF and dog platelets.
- In vivo studies in guinea pigs to assess PAF-induced thrombocytopenia and hypotension.
- Metabolism studies using liver homogenates.
Main Results:
- Pyrido[2,1-b]quinazoline-8-carboxamides with specific alkyl chains and heteroaryl moieties demonstrated potent PAF receptor inhibition.
- Enantioselective enhancement of potency was observed with an alpha-methyl group.
- (R)-enantiomer (34) exhibited superior binding affinity and greater resistance to amidase degradation.
- Racemic compound (33) effectively inhibited PAF-induced thrombocytopenia and hypotension in vivo with prolonged oral activity.
Conclusions:
- The (R)-enantiomer of a novel pyrido[2,1-b]quinazoline derivative represents a promising orally active PAF antagonist.
- This compound class shows potential for treating PAF-mediated conditions.