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 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/3-21G) 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.
Dipartimento di Scienze Farmaceutiche, Università di Bologna, Via Belmeloro 6, 40126 Bologna, Italy.
Roberta
R
Budriesi
Barbara
B
Cosimelli
Pierfranco
P
Ioan
Camilla Zaira
CZ
Lanza
Domenico
D
Spinelli
Alberto
A
Chiarini
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D016275:Atrial Function; D015220:Calcium Channels / Q000187:drug effects* / Q000378:metabolism; D002317:Cardiovascular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003864:Depression, Chemical; D005260:Female; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D066298:In Vitro Techniques; D015394:Molecular Structure; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013843:Thiazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
C463520:5-methyl-8-phenyl-8H-(1,4)thiazino(3,4-c)(1,2,4)oxadiazol-3-one; C463521:8-(4-bromophenyl)-5-methyl-8H-(1,4)thiazino(3,4-c)oxadiazol-3-one; D015220:Calcium Channels; D002317:Cardiovascular Agents; D010069:Oxadiazoles; D013843:Thiazines; D014665:Vasodilator Agents