The synthesis and cardiovascular characterization of a series of novel pyrrolo[2,1-d][1,5]benzothiazepine derivatives (54-68) are described. Selective peripheral-type benzodiazepine receptor (PBR) ligands, such as PK 11195 and Ro 5-4864, have recently been found to possess low but significant inhibitory activity of L-type calcium channels, and this property is implicated in the cardiovascular effects observed with these compounds. In functional studies both PK 11195 (1-(2-chlorophenyl)-N-methyl-N-(1- methylpropyl)-3-isoquinolinecarboxamide) and Ro 5-4864 (4'-chlorodiazepam) did not display selectivity between cardiac and vascular tissue. Therefore, several 7-(acyloxy)-6-arylpyrrolo[2,1-d][1,5]benzothiazepines, potent and selective peripheral-type benzodiazepine receptor ligands recently developed by us (3, 7-20), were subjected to calcium channel receptor binding assay. Some of these compounds showed an unexpected potency in displacing the binding of [3H]nitrendipine from L-type calcium channels, much higher than that reported for PK 11195 and Ro 5-4864 and equal to or higher than that of reference calcium antagonists such as verapamil and (+)-cis-diltiazem. Specifically, in rat cortex homogenate, our prototypic PBR ligand 7-acetoxy- 6-(p-methoxyphenyl)pyrrolo[2,1-d]-[1,5]benzothiazepine (3) showed an IC50 equal to 0.13 nM for inhibition of [3H]nitrendipine binding. Furthermore, in functional studies this compound displayed a clear-cut selectivity for cardiac over vascular tissue. Comparison of calcium antagonist activity on guinea pig aorta strips with the negative inotropic activity, determined by using isolated guinea pig left atria, revealed that 3 displayed higher selectivity than the reference (+)-cis-diltiazem. Thus, the pyrrolobenzothiazepine 3 might represent a new tool for characterizing the relationship between the PBR and cardiac function. Furthermore, we have also investigated the structural dependence of binding to PBR and L-type calcium channels, and this study allowed us to identify a new class of potent calcium channel blockers selective for cardiac over vascular tissue, with no affinity for PBR. A number of structure-activity relationship trends have been identified, and a possible explanation is advanced in order to account for the observed differences in selectivity. Three structural features, namely, (i) the saturation of the C(6)-C(7) double bond, with a consequent higher molecular flexibility, (ii) the presence of a substituent in the benzofused ring, and (iii) a basic side chain at C-10 of the pyrrolobenzothiazepine ring system, were found to be responsible for potent L-type calcium channel antagonism and clear-cut selectivity for cardiac over vascular tissue. Among the synthesized compounds the pyrrolobenzothiazepine 62 was found to be the most promising selective calcium channel blocker. Additionally, the molecular structure determination of the key intermediate 48 by X-ray diffraction, molecular modeling, and NMR analysis is reported.

Campiani, G., Fiorini, I., De Filippis, M.P., Ciani, S.M., Garofalo, A., Nacci, V., et al. (1996). Cardiovascular Characterization of Pyrrolo[2,1-d][1,5]benzothiazepine Derivatives Binding Selectively to the Peripheral-Type Benzodiazepine Receptor (PBR):  From Dual PBR Affinity and Calcium Antagonist Activity to Novel and Selective Calcium Entry Blockers. JOURNAL OF MEDICINAL CHEMISTRY, 39(15), 2922-2938 [10.1021/jm960162z].

Cardiovascular Characterization of Pyrrolo[2,1-d][1,5]benzothiazepine Derivatives Binding Selectively to the Peripheral-Type Benzodiazepine Receptor (PBR):  From Dual PBR Affinity and Calcium Antagonist Activity to Novel and Selective Calcium Entry Blockers

Campiani, Giuseppe;Fiorini, Isabella;Nacci, Vito;Giorgi, Gianluca;Sega, Alessandro;Botta, Maurizio;Bruni, Giancarlo
1996-01-01

Abstract

The synthesis and cardiovascular characterization of a series of novel pyrrolo[2,1-d][1,5]benzothiazepine derivatives (54-68) are described. Selective peripheral-type benzodiazepine receptor (PBR) ligands, such as PK 11195 and Ro 5-4864, have recently been found to possess low but significant inhibitory activity of L-type calcium channels, and this property is implicated in the cardiovascular effects observed with these compounds. In functional studies both PK 11195 (1-(2-chlorophenyl)-N-methyl-N-(1- methylpropyl)-3-isoquinolinecarboxamide) and Ro 5-4864 (4'-chlorodiazepam) did not display selectivity between cardiac and vascular tissue. Therefore, several 7-(acyloxy)-6-arylpyrrolo[2,1-d][1,5]benzothiazepines, potent and selective peripheral-type benzodiazepine receptor ligands recently developed by us (3, 7-20), were subjected to calcium channel receptor binding assay. Some of these compounds showed an unexpected potency in displacing the binding of [3H]nitrendipine from L-type calcium channels, much higher than that reported for PK 11195 and Ro 5-4864 and equal to or higher than that of reference calcium antagonists such as verapamil and (+)-cis-diltiazem. Specifically, in rat cortex homogenate, our prototypic PBR ligand 7-acetoxy- 6-(p-methoxyphenyl)pyrrolo[2,1-d]-[1,5]benzothiazepine (3) showed an IC50 equal to 0.13 nM for inhibition of [3H]nitrendipine binding. Furthermore, in functional studies this compound displayed a clear-cut selectivity for cardiac over vascular tissue. Comparison of calcium antagonist activity on guinea pig aorta strips with the negative inotropic activity, determined by using isolated guinea pig left atria, revealed that 3 displayed higher selectivity than the reference (+)-cis-diltiazem. Thus, the pyrrolobenzothiazepine 3 might represent a new tool for characterizing the relationship between the PBR and cardiac function. Furthermore, we have also investigated the structural dependence of binding to PBR and L-type calcium channels, and this study allowed us to identify a new class of potent calcium channel blockers selective for cardiac over vascular tissue, with no affinity for PBR. A number of structure-activity relationship trends have been identified, and a possible explanation is advanced in order to account for the observed differences in selectivity. Three structural features, namely, (i) the saturation of the C(6)-C(7) double bond, with a consequent higher molecular flexibility, (ii) the presence of a substituent in the benzofused ring, and (iii) a basic side chain at C-10 of the pyrrolobenzothiazepine ring system, were found to be responsible for potent L-type calcium channel antagonism and clear-cut selectivity for cardiac over vascular tissue. Among the synthesized compounds the pyrrolobenzothiazepine 62 was found to be the most promising selective calcium channel blocker. Additionally, the molecular structure determination of the key intermediate 48 by X-ray diffraction, molecular modeling, and NMR analysis is reported.
1996
Campiani, G., Fiorini, I., De Filippis, M.P., Ciani, S.M., Garofalo, A., Nacci, V., et al. (1996). Cardiovascular Characterization of Pyrrolo[2,1-d][1,5]benzothiazepine Derivatives Binding Selectively to the Peripheral-Type Benzodiazepine Receptor (PBR):  From Dual PBR Affinity and Calcium Antagonist Activity to Novel and Selective Calcium Entry Blockers. JOURNAL OF MEDICINAL CHEMISTRY, 39(15), 2922-2938 [10.1021/jm960162z].
File in questo prodotto:
File Dimensione Formato  
jm960162z.pdf

non disponibili

Tipologia: Post-print
Licenza: NON PUBBLICO - Accesso privato/ristretto
Dimensione 443.61 kB
Formato Adobe PDF
443.61 kB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11365/31316
 Attenzione

Attenzione! I dati visualizzati non sono stati sottoposti a validazione da parte dell'ateneo