AMINOPYRIDINE COMPOUNDS AND METHODS FOR THE PREPARATION AND USE THEREOF
The present invention relates generally to therapeutics targeting the bacterium Porphyromonas gingivalis , including its proteases arginine gingipain A/B (Rgp), and their use for the treatment of disorders associated with P. gingivalis infection, including brain disorders such as Alzheimer's disease. In certain embodiments, the invention provides compounds according to Formula I and Formula III, as described herein, and pharmaceutically acceptable salts thereof.
1 . A compound according to Formula III:
or a pharmaceutically acceptable salt thereof, wherein:
R 11 and R 12a are taken together to form 4- to 10-membered heterocyclyl which is optionally substituted with one or more R 17 ;
R 12b is H;
R 13a and R 13b are independently selected from the group consisting of H, —OH, and C 1-6 alkyl;
R 14 is H, or
R 14 and R 13a are taken together to form a 5- to 8-membered ring, which is optionally substituted with one or more R 18 ;
R 15a and R 15b are H;
R 16 is independently selected from the group consisting of C 1-6 alkyl and halogen;
Y is selected from the group consisting of O, S, C(R 19a ) 2 , and NR 19b ;
each R 18 is independently selected from the group consisting of C 1-6 alkyl and halogen;
each R 19a is selected from the group consisting of H and C 1-6 alkyl, or
one R 19a and R 13b are taken together to form a double bond;
R 19b is selected from the group consisting of H and C 1-6 alkyl;
subscript m is 0 or 1; and
subscript q is 0 or 1.
2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is C(R 19a ) 2 , and wherein one R 19a and R 13b are taken together to form a double bond.
3 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 14 and R 13a are taken together to form a 5- to 8-membered ring.
4 . The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 12a and R 11 are taken together to form pyrrolidin-1,2-diyl.
5 . The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein subscript q is 0.
6 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
7 . A method of treating a disease or condition associated with P. gingivalis infection, the method comprising administering to a subject in need thereof an effective amount of claim 1 , or a pharmaceutically acceptable salt thereof.
8 . The method of claim 7 , wherein the disease or condition is selected from the group consisting of a brain disorder, periodontal disease, diabetes, a cardiovascular disease, arthritis, rheumatoid arthritis, osteoarthritis, infectious arthritis, psoriatic arthritis, elevated risk of preterm birth, pneumonia, cancer, a kidney disease, a liver disease, a retinal disorder, and glaucoma.
9 . The method of claim 8 , wherein the disease or condition is a brain disorder.
10 . The method of claim 9 , wherein the brain disorder is Alzheimer's disease.
11 . The method of claim 10 , further comprising administering to the subject one or more active agents selected from the group consisting of a cholinesterase inhibitor, a serotonin modulator, an NMDA modulator, an Aβ targeted therapy, an ApoE targeted therapy, a microglia targeted therapy, a blood brain barrier targeted therapy, a tau targeted therapy, a complement targeted therapy, and an anti-inflammatory.
12 . The method of claim 8 , wherein the disease or condition is periodontal disease.
13 . The method of claim 7 , wherein the compound is administered to the subject for at least one year.
14 . The method of claim 13 , wherein the compound is administered to the subject for at least 10 years.
15 . The method of claim 7 , wherein the subject is a human, a canine, or a feline.