Inhibitors of lysine gingipain
The present invention relates generally to therapeutics targeting the bacterium Porphyromonas gingivalis , including its protease Lysine gingipain (Kgp), 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, as described herein, and pharmaceutically acceptable salts thereof.
1. A method for treating periodontal disease, the method comprising administering to a subject an effective amount of a compound according to Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
Z is halogen-substituted aryloxymethyl-carbonyl;
A is —CH 2 —;
B, D, R′, and R 2 are hydrogen;
R 3 is selected from the group consisting of C 6-10 aryl, 5-to-12 membered heteroaryl, C 3-8 cycloalkyl, 5-to-12 membered saturated heterocyclyl, and -L-R 5 , wherein
L is selected from the group consisting of —O—, —NR—, C 1-4 alkylene, and 2- to 4-membered heteroalkylene, wherein R is selected from the group consisting of hydrogen and C 1-8 alkyl,
R 5 is selected from the group consisting of C 6-10 aryl, 5-to-12 membered heteroaryl, C 3-8 cycloalkyl, and 5-to-12 membered saturated heterocyclyl,
and wherein R 3 is optionally substituted with one or more substituents selected from the group consisting of halo, —CN, —NO 2 , —N 3 , —OH, R a , R b , —OR a , —OR b , —(CH 2 ) k C(O)R c , —NR d (CH 2 ) u C(O)R c , —O(CH 2 ) u C(O)R c , —(CH 2 ) k CONR d R d , —(CH 2 ) k NR d C(O)R c , —NR d (CH 2 ) u CONR d R d , —NR d (CH 2 ) u NR d C(O)R c , —O(CH 2 ) u CONR d R d , —O(CH 2 ) u NR d C(O)R c , —(CH 2 ) k S(O) 2 NR d R d , —(CH 2 ) k NR d S(O) 2 R c , —(CH 2 ) k S(O) 2 R c , —(CH 2 ) k S(O)R c , —(CH 2 ) k SR d , —NR d (CH 2 ) n S(O) 2 NR d R d , —NR d (CH 2 ) n NR d S(O) 2 R c , —NR d (CH 2 ) u S(O) 2 R c , —NR d (CH 2 ) u S(O)R c , —NR d (CH 2 ) u SR d , —O(CH 2 ) u S(O) 2 NR d R d , —O(CH 2 ) u NR d S(O) 2 R c , —O(CH 2 ) u S(O) 2 R c , —O(CH 2 ) u S(O)R c , and —O(CH 2 ) u SR c , wherein:
each R a is independently selected from the group consisting of C 1-4 alkyl and C 1-4 haloalkyl,
each R b is independently selected from the group consisting of C 3-6 cycloalkyl, C 3-6 halocycloalkyl, C 6-10 aryl, 5-to-12 membered heteroaryl, and 5-to-12 membered saturated heterocyclyl,
each R c is independently selected from the group consisting of —OH, C 1-8 alkyl, C 1-8 haloalkyl, C 3-8 cycloalkyl, C 3-8 halocycloalkyl, C 6-10 aryl, (C 6-10 aryl)-(C 1-8 alkyl), 5-to-12 membered heteroaryl, and 5-to-12 membered saturated heterocyclyl,
each R d is independently selected from the group consisting of hydrogen and C 1-8 alkyl,
each subscript k is independently selected from 0, 1, 2, 3, 4, 5, and 6, and
each subscript u is independently selected from 1, 2, 3, 4, 5, and 6; and
R 4 is selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, and C 1-4 haloalkoxy;
provided that when A is —CH 2 —, and B and D are hydrogen, then R 3 is other than (2-phenyl)ethyl or substituted (2-phenyl)ethyl.
2. The method of claim 1 , wherein Z is halogen-substituted phenoxymethyl carbonyl.
3. The method of claim 1 , wherein R 3 is selected from the group consisting of cyclohexyl, cyclopentyl, morpholino, phenyl, piperidinyl, pyridinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydronaphthyl, and thiazolyl, each of which is optionally substituted with 1-3 members selected from the group consisting of methyl, methoxy, trifluoromethyl, acetyl, and —N 3 .
4. The method of claim 1 , wherein the compound is a compound according to Formula Id:
or a pharmaceutically acceptable salt thereof,
wherein R 3 is selected from the group consisting of C 6-10 aryl, 5-to-12 membered heteroaryl, C 3-8 cycloalkyl, 5-to-12 membered saturated heterocyclyl, and -L-R 5 ,
wherein L is C 1-4 alkylene.
5. The method of claim 4 , wherein
R 3 is selected from the group consisting of cyclohexyl, cyclopentyl, morpholino, phenyl, piperidinyl, pyridinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydronaphthyl, and thiazolyl,
each of which is optionally substituted with 1-3 members selected from the group consisting of methyl, methoxy, trifluoromethyl, acetyl, and —N 3 .
6. The method of claim 1 , wherein the compound is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
7. The method of claim 1 , wherein the compound is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
8. The method of claim 1 , wherein R 4 is selected from the group consisting of C 1-4 alkyl and C 1-4 haloalkyl.
9. The method of claim 8 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
10. The method of claim 1 , wherein the compound is administered to the subject for at least one month.
11. The method of claim 1 , wherein the subject is a human, a canine, or a feline.