New Substituted 1,4-Benzoxazine Derivatives with Potential Intracellular Calcium Activity

• Published in: Journal of medicinal chemistry Vol. 41; no. 17; pp. 3142 - 3158
• Main Authors: Bourlot, Anne-Sophie, Sánchez, Isabel, Dureng, Georges, Guillaumet, Gérald, Massingham, Roy, Monteil, André, Winslow, Eileen, Pujol, M. Dolors, Mérour, Jean-Yves
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 13.08.1998; Amer Chemical Soc
• Subjects: 1,4-Benzoxazine; Animals; Aorta - drug effects; Aorta - physiology; Biological and medical sciences; Calcium - metabolism; Calcium Channel Blockers - chemical synthesis; Calcium Channel Blockers - chemistry; Calcium Channel Blockers - pharmacology; Cardiovascular system; Chemistry, Medicinal; Drug Design; In Vitro Techniques; Life Sciences & Biomedicine; Male; Medical sciences; Miscellaneous; Molecular Structure; Muscle Contraction - drug effects; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - physiology; Oxazines - chemical synthesis; Oxazines - chemistry; Oxazines - pharmacology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Phenylephrine - pharmacology; Rabbits; Renal Artery - drug effects; Renal Artery - physiology; Science & Technology; Second Messenger Systems; Structure-Activity Relationship; Vasoconstriction - drug effects; BLOCKERS; CALMODULIN; CA2+ CHANNELS; BEPRIDIL; ATHEROSCLEROSIS; ANTIANGINAL AGENT; RABBIT AORTA; ANTAGONISTS; BINDING; VASCULAR SMOOTH-MUSCLE; Vasodilator agent; Renal artery; Calcium antagonist; Rabbit; Smooth muscle; Lagomorpha; In vitro; Vertebrata; Mammalia; Structure activity relation; Animal; Blood vessel; Bicyclic compound; Aorta; Aromatic compound; Chemical synthesis; Oxygen nitrogen heterocycle
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm970795t

Substituted 1,4-benzoxazines bearing an amino side chain at the 2-position were prepared and were found to have a moderate activity on intracellular calcium. Of the compounds studied it was found that those which possess a homoveratrylamino moiety exhibited superior potency. The chain length and the nature of the amine (4-fluorophenylpiperazine, 4-fluorobenzhydryloxyethylamine, N-substituted homoveratrylamine) is discussed. The 4-benzyl-3,4-dihydro-2-[3-[[2-(3,4-dimethoxyphenyl)ethyl]amino]propyl]-2H-1,4-benzoxazine (3c) is the most potent derivative of the series with a ratio of IC50 values against PE (phenylephrine) and K+ of 2.1. Under these test conditions a ratio near 1 indicates potential intracellular calcium activity while a ratio greater than 100 an action on extracellular calcium influx.