US EPA

7436111 

Journal Article 

Stereospecific effects of benzo[d]isothiazolyloxypropanolamine derivatives at beta-adrenoceptors: synthesis, chiral resolution, and biological activity in vitro 

Comini, M; Pozzoli, C; Incerti, M; Rossi, D; Collina, S; Azzolina, O; Di Vittorio, E; Morini, G; Poli, E 

2009 

Yes 

Chirality
ISSN: 0899-0042 

21 

2 

284-291 

English 

18537163 

10.1002/chir.20574 

WOS:000262561200005 

We performed the asymmetric synthesis of four enantiopure benzo[d] isothiazo-3-or 5-yloxypropanolamine derivatives, previously described as competitive antagonists at beta-adrenoceptors. The chemical characterization of each enantiomer was accomplished by (1)H NMR and HPLC/DAD/CD. The direct chromatographic separation of the enantiomers via chiral HPLC was investigated. The best resolutions were achieved using cellulose tris (3,5-dimethylphenyl carbamate) (Chiralcel OD-H) and amylose tris (3,5-dimethylphenyl carbamate) (Chiralpak AD). The enantiomers obtained had enantiomeric purities suitable for biological assays. Tested in isolated rat cardiac and intestinal tissues to evaluate their effects at beta(1)- and beta(3)-adrenoceptors, the (S)-enantiomers revealed a higher degree of antagonism than (R)-enantiomers at both subtypes, even though their activity was greater at the cardiac beta(1)-subtype. The potent and cardiospecific antagonistic effect exerted by the compounds tested suggests that the benzisothiazole moiety could be an interesting scaffold for discovering new chiral beta-blocking drugs. 

β-adrenoceptors; Benzisothiazoloxypropanolamines; Chiral resolution; HPLC/DAD/CD; Isolated rat tissues; 1 (3 methoxybenzo[d]isothiazol 5 yloxy) 3 (isopropylamino)propan 2 ol; 1 (tert butylamino) 3 (benzo[d]isothiazol 3 yloxy)propan 2 ol; 1,2 benzisothiazole derivative; 3 (oxiran 2 ylmethoxy)benzo[d]isothiazole; 5 (oxiran 2 ylmethoxy) 3 methoxybenzo[d]isothiazole; benzo[d]isothiazolyloxypropanolamine derivative; beta 1 adrenergic receptor; beta 3 adrenergic receptor; beta adrenergic receptor; propanolamine derivative; unclassified drug; adrenergic receptor blocking agent; propanolamine derivative; thiazole derivative; animal tissue; article; beta adrenergic receptor blocking; chiral chromatography; circular dichroism; controlled study; drug structure; drug synthesis; heart; high performance liquid chromatography; in vitro study; intestine; male; nonhuman; priority journal; proton nuclear magnetic resonance; rat; stereospecificity; animal; chemistry; chromatography; drug effect; enzyme specificity; heart atrium; ileum; isolation and purification; metabolism; stereoisomerism; synthesis; Adrenergic Antagonists; Animals; Chromatography; Chromatography, High Pressure Liquid; Circular Dichroism; Heart Atria; Ileum; Male; Propanolamines; Rats; Stereoisomerism; Substrate Specificity; Thiazoles