Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1992-10-27
1995-07-11
Warden, Jill
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 19, 530331, 548535, 546281, A61J 3806
Patent
active
054321590
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to new N-(.alpha.-substituted-pyridinyl)carbonyl-dipeptides which act as inhibitors of the angiotensin-converting enzyme. These novel compounds may be formulated, along with pharmaceutically acceptable carriers, into pharmaceutical compositions useful in the treatment of hypertension and other cardiovascular disorders whose pathophysiology involves the reninangiotensin-aldosterone system.
During the seventies, the pharmacotherapy of arterial hypertension underwent a substantial advance, due to the development of agents showing a direct action on reninangiotensin and kallikrein-kinin systems and, especially, the synthesis of the first compounds effectively inhibiting the enzymatic conversion of the decapeptide angiotensin I to the potent vasopressor angiotensin II, i.e., acting as inhibitors of the angiotensin-converting enzyme (ACE). This physiologically important enzyme also degrades the vasodilating peptide bradykinin. Several ACE inhibitors have proved capable, in experimental animals and humans, of inhibiting the pressor effects of intravenously administered angiotensin I, and have shown antihypertensive activity in animal models and hypertensive patients. Their suitability for the treatment of congestive heart failure also has convincingly been demonstrated.
U.S. Pat. No.4,105,776 discloses N-acyl derivatives of .alpha.-amino acids which are effective ACE inhibitors and, as such, useful in the treatment of hypertension. The compounds specifically concerned are mercapto derivatives of N-acyl-L-proline, including the most representative member of the series, i.e., D-3-mercapto-2-methylpropanoyl-L-proline or captopril, the first orally active ACE inhibitor antihypertensive agent made available worldwide.
Another important breakthrough in this field, but with a totally different approach, is represented by compounds disclosed in EP-A-12401, which are carboxyalkyl-dipeptide derivatives and whose more representative members are enalaprilat, enalapril and lisinopril.
A better understanding of the ACE structure and of the respective essential structural requirements for potential inhibitors, as well as an interest in providing novel compounds with different potency, kinetics and/or toxicity profiles, have led to a continuous development of new classes of ACE inhibitors. From several studies of structure-activity relationships, it has been concluded that an effective inhibition of the enzyme can only be achieved with a molecule that shows at least three clearly distinguishable regions or parts, as represented by the following general structure: ##STR2## Region A usually has a carboxyl group in the .alpha.-position, which group strongly binds to a cationic site of the enzyme structure. In several studies it has been found that L-proline is the best substructure for this region or part, although its pyrrolidine ring can also be present in a modified form.
Region B has to contain a functional group with a specific ability to bind the Zn.sup.++ cation located in the "active site" of the enzyme. This zinc-binding group, usually an acidic one, can be a mercapto group (captopril and analogues) or a carboxyl group (enalaprilat, lisinopril and analogues) as well as any precursor group which can give rise to an active group by metabolic conversion. Examples of ACE inhibitors with precursor groups are the acylthio derivatives alacepril and pivalopril and the carboxylic esters enalapril and perindopril. Some classes of inhibitors have other acidic groups in the B region, for example, --P(O)(OH)-- or --P(O)(OH)O-- in free or esterified form. In any case, all known zinc ligands are invariably linked to an alkyl group or, sometimes, to a cycloalkyl group, but never as part of an aromatic structure (M. J. Wyvratt, A. A. Patcherr, Medicinal Research Reviews 5, 483-531, 1985).
Region C acts as a bridge between the active sites of regions A and B and apparently has to satisfy definite stereochemical requirements, as the most active compounds show an L-amino acid derived unit (for example, an L-alani
REFERENCES:
Biological Abstracts, vol. 90, No. 11, 1990, AN 126221, "Synthesis of N-(2-mercaptopyridyl-3-formyl)-N-alkylglycine and the corresponding disulfides".
Cabeza Llorente Lydia
Coy Francisco Pubill
Malet Falco Carlos
Moliner Jose Repolles
Lacer S.A.
Lukton David
Warden Jill
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