Human plasma kallikrein inhibitors
Disclosed are compounds of formula I: as described herein, and pharmaceutically acceptable salts thereof. The compounds are inhibitors of plasma kallikrein. Also provided are pharmaceutical compositions comprising at least one such compound, and methods involving use of the compounds and compositions in the treatment and prevention of diseases and conditions characterized by unwanted plasma kallikrein activity.
1. A method of treating or preventing angioedema, comprising orally administering to a subject in need thereof an oral dosage form comprising a therapeutically effective amount of a compound having the structure:
wherein the compound is a bis(hydrochloride salt); and
wherein the stereochemical configuration at any chiral center is R, S, or a mixture of R and S.
2. The method of claim 1 , wherein the oral dosage form is administered once per day.
3. The method of claim 1 , wherein the oral dosage form is a capsule, and the oral dosage form is administered once per day.
4. The method of claim 1 , wherein the angioedema is hereditary angioedema.
5. The method of claim 4 , wherein the oral dosage form is administered once per day.
6. The method of claim 4 , wherein the oral dosage form is a capsule, and the oral dosage form is administered once per day.
7. The method of claim 4 , wherein the hereditary angioedema is type II hereditary angioedema.
8. The method of claim 7 , wherein the oral dosage form is administered once per day.
9. The method of claim 7 , wherein the oral dosage form is a capsule, and the oral dosage form is administered once per day.
10. The method of claim 1 , wherein the compound is the (+)-enantiomer.
11. The method of claim 10 , wherein the angioedema is hereditary angioedema.
12. The method of claim 10 , wherein the oral dosage form is administered once per day.
13. The method of claim 10 , wherein the oral dosage form is a capsule, and the oral dosage form is administered once per day.
14. The method of claim 11 , wherein the hereditary angioedema is type II hereditary angioedema.
15. The method of claim 14 , wherein the oral dosage form is administered once per day.
16. The method of claim 14 , wherein the oral dosage form is a capsule, and the oral dosage form is administered once per day.
17. The method of claim 1 , wherein the compound is the (−)-enantiomer.
18. The method of claim 17 , wherein the angioedema is hereditary angioedema.
19. The method of claim 17 , wherein the oral dosage form is administered once per day.
20. The method of claim 17 , wherein the oral dosage form is a capsule, and the oral dosage form is administered once per day.
21. The method of claim 18 , wherein the hereditary angioedema is type II hereditary angioedema.
22. The method of claim 21 , wherein the oral dosage form is administered once per day.
23. The method of claim 21 , wherein the oral dosage form is a capsule, and the oral dosage form is administered once per day.