Back to results
US 12,486,258 B2Granted
Compounds and methods for regulating insulin secretion
AssigneesThe Broad Institute, Inc., The General Hospital Corporation, Instituto Carlos Slim De La Salud, A.C.
InventorsSean M. Burns, Bridget K. Wagner, Amedeo Vetere
Life of this patent
Estimating the term…
Abstract
Disclosed herein are methods for inducing insulin secretion in a glucose-dependent manner and compounds for use in these methods.
Claims15
A method of modulating insulin secretion comprising contacting a β-cell with a compound having the structure of Formula I:
- wherein the “dashed” bond is a single or double bond;
- X1 and X2 are independently selected at each occurrence from C(R2) and N, wherein two vicinal R2 groups may together form an optionally aromatic five- or six membered fused ring;
- Y is selected from —C(O)N(R3)—, —N(R3)C(O)—, —SO2N(R3)—, and —N(R3)SO2—;
- Z1 and Z2 are independently CH2, O, N, CHR5, CR5, or NR5;
- R1 is selected from aryl, heteroaryl, heterocyclyl, and —(C(R3)2)-heterocyclyl optionally substituted with one or more substituents independently selected from alkyl, alkenyl, hydroxyalkyl, ether, acyl, and halogen, and wherein any two vicinal substituents of R1 may together form a five- or six-optionally aromatic membered ring;
- R2 is selected from hydrogen, alkyl, alkoxy, —CN, —NH2, —(CH2)1-4NH2, —(CH2)1-4N3, —(CH2)1-4NHC(O)CH3;
- and
- R3 is independently selected at each occurrence from hydrogen and alkyl optionally substituted with one to three groups independently selected from halogen, and wherein a substituent of R1 and any R4 may together form a fused five- or six-membered ring optionally substituted with one two three groups Cl, F, OH, CN, N, O, or S;
- R4 is a five- or six-membered aromatic heterocycle optionally substituted with one or more alkyl, halogen, alkoxy, and wherein any two vicinal substituents may together form an optionally aromatic five- or six-membered fused ring optionally substituted with alkyl, N, O, S, or C(═O);
- and wherein R3 may together with R2 of X1 form a five- or six membered optionally substituted fused ring;
- R5 is independently at each occurrence hydrogen or alkyl, and R5 and R2 of X2 may together form a five- or six-membered fused ring;
- and
- RQ is independently selected at each occurrence a bivalent optionally aromatic heterocycles;
- or a pharmaceutically acceptable form thereof;
- wherein insulin secretion from said B-cell occurs only when blood glucose levels exceed normoglycemic conditions.
12 more elements
A method for modulating insulin secretion comprising contacting cells with a compound having the structure of Formula I:
- wherein the “dashed” bond is a single or double bond;
- X1 and X2 are independently selected at each occurrence from C(R2) and N, wherein two vicinal R2 groups may together form an optionally aromatic five- or six membered fused ring;
- Y is selected from —C(O)N(R3)—, —N(R3)C(O)—, —SO2N(R3)—, and —N(R3)SO2—;
- Z1 and Z2 are independently CH2, O, N, CHR5, CR5, or NR5;
- R1 is selected from aryl, heteroaryl, heterocyclyl, and —(C(R3)2)-heterocyclyl optionally substituted with one or more substituents independently selected from alkyl, alkenyl, hydroxyalkyl, ether, acyl, and halogen, and wherein any two vicinal substituents of R1 may together form a five-or six-optionally aromatic membered ring;
- R2 is selected from hydrogen, alkyl, alkoxy, —CN, —NH2, —(CH2)1-4NH2, —(CH2)1-4N3, —(CH2)1-4NHC(O)CH3;
- and
- R3 is independently selected at each occurrence from hydrogen and alkyl optionally substituted with one to three groups independently selected from halogen, and wherein a substituent of R1 and any R4 may together form a fused five- or six-membered ring optionally substituted with one two three groups Cl, F, OH, CN, N, O, or S;
- R4 is a five- or six-membered aromatic heterocycle optionally substituted with one or more alkyl, halogen, alkoxy, and wherein any two vicinal substituents may together form an optionally aromatic five- or six-membered fused ring optionally substituted with alkyl, N, O, S, or C(═O);
- and wherein R3 may together with R2 of X1 form a five- or six membered optionally substituted fused ring;
- R5 is independently at each occurrence hydrogen or alkyl, and R5 and R2 of X2 may together form a five- or six-membered fused ring;
- and
- RQ is independently selected at each occurrence a bivalent optionally aromatic heterocycles;
- or a pharmaceutically acceptable form thereof.
11 more elements
Dependencies are inferred from the claim text.