ABSTRACT
As part of a program to discover potent antihypertensive analogues of diltiazem (3a), we prepared 1-benzazepin-2-ones (4). Benzazepinones competitively displace radiolabeled diltiazem, and show the same absolute stereochemical preferences at the calcium channel receptor protein. Derivatives of 4 containing a trifluoromethyl substituent in the fused aromatic ring show potent and long-acting antihypertensive activity. Studies of the metabolism of 4 lead to the metabolically stable antihypertensive calcium channel blockers 5a and 5c. Benzazepinone 5a is a longer acting and more potent antihypertensive agent than the second generation diltiazem analogue TA-3090 (3e).
Subject(s)
Antihypertensive Agents/chemical synthesis , Benzazepines/chemical synthesis , Calcium Channel Blockers/chemical synthesis , Diltiazem/analogs & derivatives , Acetylation , Animals , Antihypertensive Agents/metabolism , Antihypertensive Agents/therapeutic use , Aorta/drug effects , Aorta/physiology , Benzazepines/metabolism , Benzazepines/therapeutic use , Calcium Channel Blockers/metabolism , Calcium Channel Blockers/therapeutic use , Diltiazem/chemistry , Diltiazem/therapeutic use , Guinea Pigs , Hypertension/drug therapy , Male , Microsomes, Liver/metabolism , Molecular Conformation , Molecular Structure , Pyrrolidines/chemical synthesis , Pyrrolidines/therapeutic use , Rabbits , Rats , Rats, Inbred SHR , Structure-Activity Relationship , Vasodilation/drug effectsABSTRACT
We have synthesized a series of benzazepinones (2) in order to determine the structure-activity relationships (SAR) for calcium channel blockers related to diltiazem. A prerequisite for calcium channel blocking activity in vitro and in vivo is the presence of two pharmacophores: a 4'-aryl methyl ether and a basic substituent appended to N1 with a pKa in the physiological range. When these constraints are satisfied, a wide variety of substitution is tolerated at C6, C7, and C3. The presence of an electron-withdrawing group at C6 appears to enhance potency in vitro and in vivo. For such benzazepinones, activity is primarily dependent upon lipophilicity, as measured by log P. We believe these compounds must partition into the cell membrane in order to access their receptor. The quaternary methiodide 15k was used to demonstrate that the binding site for benzazepinones is on the intracellular face of the membrane. This work represents the first comprehensive SAR of diltiazem-like calcium channel blockers.
Subject(s)
Benzazepines/chemistry , Calcium Channel Blockers/chemistry , Diltiazem/analogs & derivatives , Benzazepines/metabolism , Binding Sites , Calcium Channel Blockers/metabolism , Calcium Channels/metabolism , Cell Membrane/metabolism , Chemical Phenomena , Chemistry, Physical , Molecular Structure , Structure-Activity RelationshipABSTRACT
Substituted 1,2,3,4-tetrahydroaminonaphthols were found to be calcium channel blockers with antihypertensive properties. These compounds also possessed adrenergic beta-receptor blocking activity. From the structure-activity studies, no clear correlation emerged between the in vitro calcium channel blocking activity and the acute anti-hypertensive activity in cannulated spontaneously hypertensive rats. Extensive pharmacological testing of selected compounds indicated that aminonaphthols are antihypertensive agents with many pharmacological properties. The relative contribution of various pharmacological actions toward the observed antihypertensive activity is unclear. Since the clinically useful calcium channel blocker verapamil is structurally related to these compounds, one of the aminonaphthols, trans-3-[(3,3-diphenylpropyl)amino]-1,2,3,4-tetrahydro-6,7 -dimethoxy-2-naphthalenol (12), was compared with verapamil for calcium channel blocking activity, adrenergic blocking activity, and catecholamine-depleting activity. Both compounds were found to be equipotent in these test systems.
Subject(s)
Adrenergic beta-Antagonists/pharmacology , Antihypertensive Agents/pharmacology , Calcium Channel Blockers/pharmacology , Catecholamines/metabolism , Naphthalenes/pharmacology , Naphthols/pharmacology , Tetrahydronaphthalenes/pharmacology , Action Potentials/drug effects , Adrenergic beta-Antagonists/chemical synthesis , Animals , Antihypertensive Agents/chemical synthesis , Blood Pressure/drug effects , Calcium Channel Blockers/chemical synthesis , Cattle , Female , Ion Channels/drug effects , Male , Naphthols/chemical synthesis , Rabbits , Rats , Rats, Inbred SHR , Receptors, Adrenergic, beta/drug effects , Structure-Activity Relationship , Swine , Tetrahydronaphthalenes/chemical synthesis , Verapamil/pharmacologyABSTRACT
The synthesis and CNS activity of a series of 34 substituted bicyclic pyrazolines are described. Ten of these compounds were also screened for antiinflammatory activity. One of the compounds (15) exhibited significant antiinflammatory activity in the carrageenan-induced edema test.
