GLP-1 receptor stabilizers and modulators
Compounds that bind the glucagon-like peptide 1 (GLP-1) receptor, methods of their synthesis, methods of their therapeutic and/or prophylactic use, and methods of their use in stabilizing GLP-1 receptor in vitro for crystallization of the GLP-1 receptor are provided. Certain compounds may have activity as modulators or potentiators with respect to glucagon receptor, GIP receptor, GLP-1 and GLP-2 receptors, and PTH receptor on their own or in the presence of receptor ligands such as GIP(1-42), PTH(1-34), Glucagon(1-29), GLP-2(1-33), GLP-1(7-36), GLP-1(9-36), oxyntomodulin and exendin variants.
1. A method of treating type II diabetes in a subject in need thereof, said method comprising administering to said subject a pharmaceutical composition comprising a compound having a structure of Formula I:
or a pharmaceutically acceptable salt thereof, wherein
each of X 1A , X 1B , X 2A and X 2B is CH;
R 4 is H, alkyl, alkoxy, alkyl substituted with one or more R 43 , halogen, perhaloalkyl, perhaloalkoxy, —CN, —OR 40 , or —NR 41 R 42 ;
W 1 is -L 1 -CH 2 —R 1 ;
L 1 is —NH—C(O)—;
R 1 is R 13 ;
each R 10 , R 11 and R 12 is independently H or alkyl;
R 13 is phenyl, where any ring atom of R 13 may be optionally substituted with one or more R 14 or R 15 ;
each R 14 is independently H, alkyl, halo, hydroxy, cyano, alkoxy, perhaloalkyl, perhaloalkoxy, —OR 10 , —(CH 2 ) n —COOR 10 , —SR 10 , —SO—R 10 , —SO 2 R 10 , —(CH 2 ) n —NR 11 R 12 , —NHCO(CH 2 ) n —R 12 , —N(R 11 )CO(CH 2 ) n —R 12 , or —NH(CH 2 ) n —R 12 ;
each R 15 is cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, or a fused bicycle of any two of such ring moieties, where any ring atom of R 15 may be optionally substituted with one or more R 14 ;
R 5 is independently H, alkyl, alkoxy, alkyl substituted with one or more R 53 , halogen, perhaloalkyl, perhaloalkoxy, —CN, —OR 50 , or —NR 51 R 52 ;
W 2 is -L 2 -R 2 ;
L 2 is 1,2,4-oxadiazol-3-yl;
each R a and R b is independently H, hydroxy, methyl, or both R a and R b attached to the same carbon are, taken together, oxo, or cycloalkyl;
R 2 is R 26 , —O—(CH 2 ) n —R 26 , R 23 or -L 4 -R 23 ;
L 4 is —O—(CH 2 ) n —, —C≡C—, —C(O)NR 20 —(CH 2 ) n —, —N(R 20 )—C(O)—(CH 2 ) n —, —N(R 20 )—S(O 2 )—, —S(O 2 )—NR 20 —, or cyclopropylene;
each R 20 is independently H or alkyl;
R 23 is cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, or a fused bicycle of any two of such ring moieties, or R 23 and R 20 taken together with the N atom to which they are attached form a heterocyclic ring optionally fused with aryl or heteroaryl, where any ring atom of R 23 may be optionally substituted with one or more of R 24 and wherein one ring atom of R 23 is optionally substituted with -L 3 -R 25 ;
each R 24 is independently H, halo, alkyl, hydroxy, oxo, cyano, alkoxy, perhaloalkyl, perhaloalkoxy, nitro or amino, —O—(CH 2 ) n —R 21 , —(CH 2 ) n —O—R 21 , —O(CH 2 ) n —O—R 21 , —(CH 2 ) n —NR 21 R 22 , —(CH 2 ) n —N(R 21 )CO(CH 2 ) n —R 21 , —(CH 2 ) n —N(R 21 )SO 2 (CH 2 ) n —R 21 , —(CH 2 ) n —SO 2 —N(R 21 )—(CH 2 ) n —R 21 , —(CH 2 ) n —CO(CH 2 ) n —R 21 , —(CH 2 ) m —COO—R 21 , —O—(CH 2 ) n —COO—R 21 or —(CH 2 ) m —OCO—R 21 ;
each R 21 and R 22 is independently H, alkyl, or —(CH 2 ) n —COOH, or R 21 and R 22 taken together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocyclic ring;
L 3 is null, —O—, —(CH 2 ) n —O—(CH 2 ) n —, or —(CH 2 ) n —NR 20 —(CH 2 ) n —;
each R 25 is independently cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, or a fused bicycle of any two of such ring moieties 1, where any ring atom of R 25 may be optionally substituted with one or more of R 24 ;
R 26 is H, alkyl, alkoxy, oxo, hydroxy, or hydroxy substituted alkyl;
Y is —C(O)—, —CH 2 —, —C(O)—CH 2 —, or —CH 2 —C(O)—;
Z is —(CR a R b ) n —C(O)—R 3 , —(CR a R b ) n —R 3 , —R 34 —C(O)—R 3 , or H;
R 3 is —OR 30 , —NR 31 R 32 or —(CO)NHSO 2 R 30 ;
each R 30 is independently H or alkyl;
each R 31 and R 32 is independently H or C 1 -C 6 alkyl optionally substituted with one or more R 33 , or R 31 and R 32 taken together with the N atom to which they are attached form a 3- to 7-membered heterocyclic ring;
each R 33 is independently halo, hydroxyl, alkoxy, perhaloalkyl, perhaloalkoxy, carboxyl, —COO—R 30 , or —OR 30 ;
R 34 is cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, where any ring atom of R 34 may be optionally substituted with one or more R 35 ;
each R 35 is independently H, alkyl, halo, hydroxy, cyano, alkoxy or perhaloalkyl;
each R 40 and R 50 is independently H or alkyl;
each R 41 and R 42 is independently H, alkyl, —(CH 2 ) n —COO—R 40 , —C(O)—R 40 , aryl, or heteroaryl, or R 41 and R 42 taken together with the N atom to which they are attached form a 3- to 7-membered heterocyclic ring;
each R 51 and R 52 is independently H or alkyl, —(CH 2 ) n —COO—R 50 , —C(O)—R 50 , aryl, heteroaryl, or R 51 and R 52 taken together with the N atom to which they are attached form a 3- to 7-membered heterocyclic ring;
each R 43 is independently H, halo, hydroxyl, —NR 41 R 42 , or alkoxy;
each R 53 is independently H, halo, hydroxyl, —NR 51 R 52 , or alkoxy;
k is 1, 2, 3 or 4;
each m is independently 0 or 1;
each n is independently 0, 1, 2, 3 or 4;
wherein each occurrence of heterocyclyl is independently an aromatic or non-aromatic ring moiety, mono-cyclic or fused poly-cyclic, containing 3 to 20 ring members and with at least one heteroatom selected from N, O, S and P; and
wherein each occurrence of heteroaryl is independently an aromatic ring moiety, mono-cylic or fused poly-cyclic, containing 5 to 20 ring members and with at least one heteroatom selected from N, O, S and P, and in the case of a fused poly-cyclic heteroaryl at least one ring is aromatic.
2. The method of claim 1 wherein the subject is a human being.
3. The method of claim 1 , wherein the compound has the structure of Formula II:
or a pharmaceutically acceptable salt thereof, wherein
R 1 is R 13 ;
each R 10 , R 11 and R 12 is independently H or alkyl;
R 13 is phenyl, where any ring atom of R 13 may be optionally substituted with one or more R 14 or R 15 ;
each R 14 is independently H, alkyl, halo, hydroxy, cyano, alkoxy, perhaloalkyl, perhaloalkoxy, —OR 10 , —(CH 2 ) n —COOR 10 , —SR 10 , —SO—R 10 , —SO 2 R 10 , —NR 11 R 12 , —NHCO(CH 2 ) n —R 12 , —N(R 11 )CO(CH 2 ) n —R 12 , or —NH(CH 2 ) n R 12 ;
each R 15 is cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, or a fused bicycle of any two of such ring moieties, where any ring atom of R 15 may be optionally substituted with one or more R 14 ;
L 2 is 1,2,4-oxadiazol-3-yl;
R 2 is R 26 , —O—(CH 2 ) n —R 26 , R 23 or —O—(CH 2 ) n —R 23 ;
each R 20 is independently H or alkyl;
R 23 is cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, or a fused bicycle of any two of such ring moieties;
each R 24 is independently H, halo, alkyl, hydroxy, oxo, cyano, alkoxy, perhaloalkyl, perhaloalkoxy, nitro or amino, —O—(CH 2 ) n —R 21 , —(CH 2 ) n —O—R 21 , —O—(CH 2 ) n —O—R 21 , —(CH 2 ) n —NR 21 R 22 , —(CH 2 ) n —N(R 21 )CO(CH 2 ) n —R 21 , —(CH 2 ) n —N(R 21 )SO 2 (CH 2 ) n —R 21 , —(CH 2 ) n —SO 2 —N(R 21 )—(CH 2 ) n —R 21 , —(CH 2 ) n —CO(CH 2 ) n —R 21 , —(CH 2 ) m —COO—R 21 , —O—(CH 2 ) n —COO—R 21 or —(CH 2 ) m —OCO—R 21 ;
each R 21 and R 22 is independently H, alkyl, —(CH 2 ) n —COOH, or R 21 and R 22 taken together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocyclic ring;
L 3 is null, —O—, —(CH 2 ) n —O—(CH 2 ) n —, or —(CH 2 ) b —NR 20 —(CH 2 ) n —;
each R 25 is independently cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, or a fused bicycle of any two of such ring moieties 1, where any ring atom of R 25 may be optionally substituted with one or more of R 24 ;
each R 26 is independently H, alkyl, alkoxy, oxo, hydroxy, or hydroxy substituted alkyl;
Z is —(CH 2 ) n —C(O)—R 3 , —(CH 2 ) n —R 3 , —R 34 —C(O)—R 3 or H;
R 34 is cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, where any ring atom of R 34 may be optionally substituted with one or more R 35 ;
each R 35 is independently H, alkyl, halo, hydroxy, cyano, alkoxy or perhaloalkyl;
R 3 is —OR 30 , or —NR 31 R 32 ;
each R 30 is independently H or alkyl;
each R 31 and R 32 is independently H or C 1 -C 6 alkyl optionally substituted with one or more R 33 , or R 31 and R 32 taken together with the N atom to which they are attached form a 3- to 7-membered heterocyclic ring;
each R 33 is independently halo, hydroxyl, alkoxy, perhaloalkyl, perhaloalkoxy, carboxyl, —COO—R 30 , or —OR 30 ;
each m is independently 0 or 1;
each n is independently 0, 1, 2, 3 or 4;
wherein each occurrence of heterocyclyl is independently an aromatic or non-aromatic ring moiety, mono-cyclic or fused poly-cyclic, containing 3 to 20 ring members and with at least one heteroatom selected from N, O, S and P; and
wherein each occurrence of heteroaryl is independently an aromatic ring moiety, mono-cylic or fused poly-cyclic, containing 5 to 20 ring members and with at least one heteroatom selected from N, O, S and P, and in the case of a fused poly-cyclic heteroaryl at least one ring is aromatic.
4. The method of claim 3 wherein R 1 is substituted with one or more substituents selected independently from the group consisting of methyl, ethyl, isopropyl, t-butyl, —CF 3 , methoxy, ethoxy, hydroxyl, —OCF 3 , halogen, methylthio, and —SO 2 CH 3 .
5. The method of claim 4 wherein R 1 is substituted with one or more substituents selected independently from the group consisting of methyl, methoxy, and —CF 3 .
6. The method of claim 4 wherein R 1 is
7. The method of claim 1 wherein the compound is selected from one of the following compounds:
or any pharmaceutically acceptable salt thereof.
8. The method of claim 1 wherein the compound is selected from one of the following compounds:
or any pharmaceutically acceptable salt thereof.