PCSK9 antagonists bicyclo-compounds
Disclosed are compounds of Formula I, or a salt thereof cyclic polypeptide of Formula I: Formula I where A, B, E, R 4 , and R 8 are as defined herein, which compounds have properties for antagonizing PCSK9. Also described are pharmaceutical formulations comprising the compounds of Formula I or their salts, and methods of treating cardiovascular disease and conditions related to PCSK9 activity, e.g. atherosclerosis, hypercholesterolemia, coronary heart disease, metabolic syndrome, acute coronary syndrome, or related cardiovascular disease and cardiometabolic conditions
1. A compound of the Formula I:
wherein:
R 4 is: (a) linear, branched or cyclic alkyl of up to 6 carbon atoms; (b) —(CH 2 ) x —R 13B , wherein: x is 1-4, and R 13B is —NH 2 or —N + H 3 ; (c) —(CH 2 ) x —R 13C , wherein: x is 1-4, and R 13C is —N(R 13D ) 2 or —N(R 13D ) 3 wherein R 13D is a linear or branched alkyl of up to 4 carbon atoms; (d) —CH 2 NH—C(O)—O—C(CH 3 ) 3 ; or
(e) —CH 2 —NH—C(O)—[(CH 2 ) 2 —O—] y —(CH 2 ) 2 —R 13E , wherein, y is 1 to 4 and R 13E is —NH 2 , —N + H 3 , or —N + (CH 3 ) 3 ;
R 8 is a moiety of the formula:
wherein R 8a is —H, or a linear, branched or cyclic alkyl of up to four carbon atoms;
A is (a) —CH 2 —; or
(b) a moiety of the formula:
wherein R 3 is:
(i) linear, branched or cyclic alkyl of up to 6 carbon atoms;
(ii) —(CH 2 ) z —R 14A , wherein: z is 1-4, and R 14A is —NH 2 or —N + H 3 ;
(iii) —(CH 2 ) z —R 14B , wherein: z is 1-4, and R 14B is —N(CH 3 ) 2 or —N + (CH 3 ) 3 ; or
(iv) —CH 2 —NH—C(O)—[(CH 2 ) y —O—] 2 —(CH 2 ) 2 —R 14C wherein, y′ is 1 to 6, and R 14C is —NH 2 , —N + H 3 , or —N + (CH 3 ) 3 ;
B is:
(a) a moiety of the formula:
wherein:
R 1 is —H or —NH—C(O)—CH 3 ;
R 2 is —H or —C(O)—R 15A , wherein R 15A is —NH 2 , —N + H 3 , or —N + (CH 3 ) 3 ; and
C 1 is —CH 2 — or —(CH 2 ) 2 —O—; or
(b) a moiety of the formula:
D is:
(a) a moiety of the formula:
or
(b) a moiety of the formula:
wherein R 12 is —H or —CH 3 ; and
E is:
(a) a moiety of the formula:
or
(b) a moiety of the formula:
or a pharmaceutically acceptable salt thereof.
2. A compound of claim 1 having the formula of Formula II:
or a pharmaceutically acceptable salt thereof.
3. A compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 4 is:
(a) —CH 3 ;
(b) —CH(CH 3 ) 2 ;
(c) —(CH 2 ) x —R 13b , wherein: x is 1-4, and R 13b is —NH 2 or —N + H 3 ; (d) —CH 2 NH—C(O)—O—C(CH 3 ) 3 ; or (iv) —CH 2 —NH—C(O)—[(CH 2 ) 2 —O—] 2 —(CH 2 ) 2 —R 13 , wherein R 13c is —NH 2 , —N + H 3 , or —N + (CH 3 ) 3 .
4. A compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 8 is a moiety of the formula:
wherein R 8b is —H, —CH 3 , or —C(CH 3 ) 3 .
5. A compound of claim 2 , or a pharmaceutically acceptable salt thereof,
Wherein:
A is a moiety of the formula:
and
R 3 is
(i) —CH 3 ;
(ii) —CH(CH 3 ) 2 ;
(iii) —(CH 2 ) z —R 13a , wherein: z is 1-4, and R 13a is —NH 2 or —N + H 3 ; or
(iv) —CH 2 —NH—C(O)—[(CH 2 ) 2 —O—] 2 —(CH 2 ) 2 —R 13c , wherein R 13c is —NH 2 , —N + H 3 , or —N + (CH 3 ) 3 .
6. A compound of claim 2 having the formula of Formula III:
or a pharmaceutically acceptable salt thereof.
7. A compound of claim 1 having the Formula IV:
wherein:
B 2 is:
(a) a moiety of the formula:
or
(b) a moiety of the formula:
wherein:
R 1 is —H or —NH—C(O)—CH 3 ;
R 2 is —H or —C(O)—R 16A NH 2 R 16A is —NH 2 , —N + H 3 , —N(CH 3 ) 2 , or —N + (CH 3 ) 3 ,
or a pharmaceutically acceptable salt thereof.
8. A compound of claim 1 , which is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
9. A compound of claim 1 , which is selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
10. A composition comprising at least one compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
11. A method of treating hypercholesterolemia, comprising administering to a patient in need thereof a therapeutically effective amount of a composition of claim 10 .
12. A method of treating hypercholesterolemia, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 .
13. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, for use in therapy.
14. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, for treating hypercholesterolemia.
15. A compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.