Dual ACE C-domain/NEP inhibitors
A superior dual ACE/NEP inhibitor is a combination that selectively targets the ACE C-domain in addition to inhibiting NEP. Such a dual ACE C-domain/NEP inhibitor can be used in the treatment of diverse cardiovascular diseases, including hypertension and heart failure.
1. A selective dual ACE/NEP inhibitor comprising Lis-Trp and sacubitrilat, wherein the dual ACE/NEP inhibitor is selective for the C-domain active site of ACE and for the NEP active site; and wherein Lis-Trp is modified Lisinopril comprising a tryptophan moiety in position P 2 ′ that confers angiotensin-converting enzyme selectivity for the C-domain active site sufficient to inhibit the conversion of angiotensin I to angiotensin II whilst preserving bradykinin metabolism.
2. The dual ACE/NEP inhibitor as claimed in claim 1 , wherein the dual ACE/NEP inhibitor is provided in a pharmaceutical composition further comprising a pharmaceutically acceptable carrier, together with other optional pharmaceutically acceptable excipients.
3. The dual ACE/NEP inhibitor as claimed in claim 2 , wherein the pharmaceutical composition is in the form of a tablet or capsule for oral administration.
4. The dual ACE/NEP inhibitor as claimed in claim 2 , wherein the pharmaceutical composition is in a form for administration by a parenteral route.
5. A method of treating a cardiovascular disease,
wherein the cardiovascular disease is selected from:
a. hypertension (high blood pressure);
b. heart failure, including congestive heart failure, heart failure with reduced left ventricular (LV) ejection fraction (HFrEF), heart failure with preserved LV ejection fraction (HFpEF), left ventricular dysfunction, right-sided heart failure, right ventricular dysfunction, and general states of reduced cardiac output;
c. atherosclerosis and atherosclerotic vascular disease, including coronary heart disease and coronary artery disease;
d. myocardial infarction (heart attack), including acute coronary syndrome;
e. nephropathy (kidney dysfunction) associated with hypertension or diabetes;
f. stroke, including infarction of the brain or any part of the brain due to cerebral artery occlusion, thrombosis, or haemorrhage,
comprising administering to a patient in need of such treatment a therapeutically effective amount of a selective dual ACE/NEP inhibitor comprising Lis-Trp and sacubitrilat, the dual ACE/NEP inhibitor being selective for the C-domain active site of ACE and for the NEP active site; and wherein Lis-Trp is modified Lisinopril comprising a tryptophan moiety in position P 2 ′ that confers angiotensin-converting enzyme selectivity for the C-domain active site sufficient to inhibit the conversion of angiotensin I to angiotensin II whilst preserving bradykinin metabolism.
6. The method of claim 5 , wherein the dual ACE C-domain/NEP inhibitor is administered by an oral route in the form of a tablet, capsule, or other pharmaceutical formulation suitable for oral administration.
7. The method of claim 6 , wherein the oral administration is once per day, twice per day, three times per day, or four times per day.
8. The method of claim 5 , wherein the dual ACE C-domain/NEP inhibitor is administered by a parenteral route in a pharmaceutical formulation suitable for parenteral administration.
9. The method of claim 8 , wherein parenteral administration is intravenously, intramuscularly, or subcutaneously.
10. The method of claim 8 , wherein the parenteral administration is once per day, twice per day, three times per day, or four times per day.
11. A composition comprising a combination of Lis-Trp, an inhibitor selective for the C-domain active site of ACE and sacubitrilat, an inhibitor of the NEP active site, Lis-Trp being modified Lisinopril comprising a tryptophan moiety in position P 2 ′ that confers angiotensin-converting enzyme selectivity for the C-domain active site sufficient to inhibit the conversion of angiotensin I to angiotensin II and the breakdown of natriuretic peptides whilst preserving bradykinin metabolism.
12. A method for treatment of a cardiovascular disease comprising administering a composition according to claim 11 , where such cardiovascular disease is selected from:
a. hypertension (high blood pressure);
b. heart failure, including congestive heart failure, heart failure with reduced left ventricular (LV) ejection fraction (HFrEF), heart failure with preserved LV ejection fraction (HFpEF), left ventricular dysfunction, right-sided heart failure, right ventricular dysfunction, and general states of reduced cardiac output;
c. atherosclerosis and atherosclerotic vascular disease, including coronary heart disease and coronary artery disease;
d. myocardial infarction (heart attack), including acute coronary syndrome;
e. nephropathy (kidney dysfunction) associated with hypertension or diabetes;
f. stroke, including infarction of the brain or any part of the brain due to cerebral artery occlusion, thrombosis, or hemorrhage.
13. The method of claim 12 , wherein the composition is administered by an oral route in a form that combines both compounds (the ACE C-domain inhibitor and the NEP inhibitor) in a single formulation, where such formulation is a tablet, capsule, or other pharmaceutical formulation suitable for oral administration.
14. The method of claim 13 , wherein the oral administration is once per day, twice per day, three times per day, or four times per day.
15. The method of claim 12 , wherein the combination is administered by a parenteral route, in a pharmaceutical formulation that combines both compounds (the ACE C-domain inhibitor and the NEP inhibitor) in a single formulation suitable for parenteral administration.
16. The method of claim 15 , wherein the parenteral administration is intravenously, intramuscularly, or subcutaneously.
17. The method of claim 15 , wherein the parenteral administration is once per day, twice per day, three times per day, or four times per day.