Cardiovascular Characterization of [1,4]Thiazino[3,4-c][1,2,4]oxadiazol-1-one Derivatives:  Selective Myocardial Calcium Channel Modulators

As an extension of previous investigations (Tetrahedron 1999, 55, 5433−5440; J. Heterocycl. Chem. 2000, 37, 875−878), a series of 21 [1,4]thiazino[3,4-c][1,2,4]oxadiazolones, which has already been synthesized (except for compounds 5a, 5b, 6), was evaluated as calcium entry blockers by functional st...

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Published in:Journal of medicinal chemistry 2002-08, Vol.45 (16), p.3475-3481
Main Authors: Budriesi, Roberta, Cosimelli, Barbara, Ioan, Pierfranco, Lanza, Camilla Zaira, Spinelli, Domenico, Chiarini, Alberto
Format: Article
Language:English
Subjects:
Animals
Aorta, Thoracic - drug effects
Aorta, Thoracic - physiology
Atrial Function
Biological and medical sciences
Calcium Channels - drug effects
Calcium Channels - metabolism
Cardiovascular Agents - chemical synthesis
Cardiovascular Agents - chemistry
Cardiovascular Agents - pharmacology
Cardiovascular system
Depression, Chemical
Female
Guinea Pigs
Heart Atria - drug effects
In Vitro Techniques
Medical sciences
Miscellaneous
Molecular Structure
Myocardial Contraction - drug effects
Myocardium - metabolism
Oxadiazoles - chemical synthesis
Oxadiazoles - chemistry
Oxadiazoles - pharmacology
Pharmacology. Drug treatments
Structure-Activity Relationship
Thiazines - chemical synthesis
Thiazines - chemistry
Thiazines - pharmacology
Vasodilator Agents - chemical synthesis
Vasodilator Agents - chemistry
Vasodilator Agents - pharmacology
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Summary:As an extension of previous investigations (Tetrahedron 1999, 55, 5433−5440; J. Heterocycl. Chem. 2000, 37, 875−878), a series of 21 [1,4]thiazino[3,4-c][1,2,4]oxadiazolones, which has already been synthesized (except for compounds 5a, 5b, 6), was evaluated as calcium entry blockers by functional studies, namely, in isolated guinea-pig left and right atria and K+-depolarized aortic strips. With the aim of investigating the effect of a condensed benzene ring on the molecular structure and the influence of substituents on the 8-phenyl ring of 4a, ab initio computations (RHF/3-21*G) were performed on compounds 3, 4a−d, 4f, and 4k. The results obtained show that many of the compounds studied are potent and selective negative inotropic agents; in particular, compounds 4e and 4f are about 3- and 2-fold more potent than diltiazem, respectively.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm020815d