Inhibitors of sarm1 nadase activity and uses thereof
AssigneesWashington University, Disarm Therapeutics, Inc.
InventorsJeffrey MILBRANDT, Kow ESSUMAN, Yo SASAKI, Aaron DIANTONIO, Xianrong MAO, Rajesh DEVRAJ, Raul Eduardo KRAUSS, Robert Owen HUGHES
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Abstract
The present disclosure provides compounds useful as inhibitors of SARM1 NADase activity, compositions thereof, and methods of using the same. The present disclosure provides compounds useful for treating a neurodegenerative or neurological disease or disorder, compositions thereof, and methods of using the same.
Claims145
A method of inhibiting SARM1 NADase activity and/or treating a neurodegenerative or neurological disease or disorder in a patient in need thereof, comprising administering to said patient the composition according to formula IA:
- or a pharmaceutically acceptable salt thereof, wherein:
- XA is —S—, —SO— or —SO2—;
- R1A is hydrogen, C1-4 aliphatic, alkali metal, alkaline earth metal, ammonium or N+(C1-4alkyl)4;
- Ring AA is selected from a benzo fused ring and a 5-6 membered heteroaromatic fused ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
- Ring BA is selected from phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
- RXA and RYA are independently hydrogen, C1-4 aliphatic optionally substituted with 1-4 halogen, —ORA, —SRA, —N(RA)2, —N(RA)C(O)RA, —C(O)N(RA)2, —N(RA)C(O)N(RA)2, —N(RA)C(O)ORA, —OC(O)N(RA)2, —N(R)S(O)2RA, —S(O)2N(RA)2, —C(O)RA, —C(O)ORA, —OC(O)RA, —S(O)RA, —S(O)2RA, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
- each RA is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
- mA and nA are independently 0, 1, 2, or 3.
A method of inhibiting SARM1 NADase activity and/or treating a neurodegenerative or neurological disease or disorder in a patient in need thereof, comprising administering to said patient the composition according to formula IB:
- or a pharmaceutically acceptable salt thereof, wherein:
- X1B and X2B are independently —O—, —S—, or —NRB—, provided that one of X1B and X2B is —O— or —S— and both of X1B and X2B are not —O—;
- YB is —N— or —CH—;
- each R1B is independently hydrogen or optionally substituted C1-4 aliphatic;
- Ring AB is selected from phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
- each RXB is independently hydrogen, halogen or an optionally substituted group selected from C1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
- each RB is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
- LB is a covalent bond, a C1-6 membered straight or branched bivalent hydrocarbon chain, cyclopropylenyl, cyclobutylenyl, or oxetanylenyl;
- and
- nB is 0, 1, 2, 3 or 4.
A method of identifying a SARM1 NADase inhibitor, comprising:
- a. providing a mixture comprising i) a mutant or fragment of SARM1, ii) NAD+ and iii) a candidate inhibitor, wherein the mutant or fragment has constitutive NADase activity;
- b. incubating the mixture;
- c. quantifying NAD+ and ADPR in the mixture after the incubating;
- d. determining the molar ratio of NAD+:ADPR;
- and
- e. identifying the candidate inhibitor compound as an NADase inhibitor if the molar ratio is greater than that of a control mixture that does not contain the candidate inhibitor.
A polypeptide consisting of a mutant or fragment of SARM1, wherein the mutant or fragment has constitutive NADase activity.
A polypeptide consisting of:
- a mutant or fragment of SARM1, wherein the mutant or fragment has constitutive NADase activity;
- and
- at least one tag.
A polypeptide having constitutive NADase activity and at least 70% sequence identity with a sequence of a fragment of human SARM1 that has constitutive NADase activity.
A fragment of human SARM1 that has constitutive NADase activity.
A method of identifying a SARM1 NADase inhibitor, comprising:
- a. providing a mixture comprising i) at least one cultured neuron comprising at least one axon and ii) a candidate SARM1 NADase inhibitor;
- b. adding a labeled NAM to the mixture;
- c. transecting the at least one axon;
- d. quantifying the amount of labeled and unlabeled NAD+ in the mixture;
- and
- e. identifying an inhibitor of SARM1 NADase when the post-injury NAD+ consumption rate is decreased compared to that of a control mixture that does not contain the candidate inhibitor.
A method of identifying an inhibitor of axonal degeneration, comprising:
- a. providing a mixture comprising i) at least one cultured neuron comprising an axon and ii) a candidate inhibitor;
- b. disrupting the neuron;
- c. calculating a degeneration index using at least one microscope image;
- and
- d. identifying an inhibitor of axon degeneration when there is a statistically significant decrease in the degeneration index compared to that of a control.
A method of identifying a SARM1 NADase inhibitor, comprising:
- a. providing a mixture comprising i) a mutant or fragment of SARM1, ii) NAD+ and iii) a candidate inhibitor, wherein the mutant or fragment has constitutive NADase activity;
- b. incubating the mixture;
- c. quantifying NAD+ in the mixture after the incubating;
- and
- d. identifying the candidate inhibitor compound as an NADase inhibitor if the amount of NAD+ is greater than that of a control mixture that does not contain the candidate inhibitor.
A method of treating an axonopathy, comprising administering a pharmaceutically effective amount of an inhibitor of SARM1 NADase activity.
A method of inhibiting SARM1 NADase activity, comprising contacting SARM1 with a SARM1 NADase inhibitor.
A method of treating an axonopathy, comprising administering to a subject in need thereof a therapeutically effective amount of an inhibitor of SARM1 NADase activity.
A method of treating an axonopathy, comprising administering to a subject in need thereof a therapeutically effective amount of Nicotinamide Hypoxanthine dinucleotide (NHD).
A method of identifying a SARM1 NADase inhibitor, comprising:
- a) providing a mixture comprising i) a polypeptide that has at least 70% sequence identity with a fragment of human SARM1 that has constitutive NADase activity, ii) NAD+ and iii) a candidate inhibitor, wherein the polypeptide has constitutive NADase activity;
- b) incubating the mixture;
- c) quantifying NAD+ and at least one NADase cleavage product in the mixture after the incubating;
- and
- d) identifying the candidate inhibitor compound as an NADase inhibitor if the molar ratio of NAD+ to the at least one NADase cleavage product is greater than that of a control mixture that does not contain the candidate inhibitor.
A method of inhibiting SARM1 NADase activity comprising contacting a SARM1 polypeptide with a proton pump inhibitor.
A method of inhibiting SARM1 NADase activity comprising contacting a SARM1 polypeptide with a compound of formula IC:
- or a pharmaceutically acceptable salt thereof,
- wherein:
- XC is N or C;
- R1C is H, C1-C5 alkyl, C1-C5 alkoxy, or C1-C5 haloalkoxy;
- R2C is C1-C5 alkyl or C1-C5 alkoxy;
- R3C is C1-C10 alkyl, C1-C10 haloalkyl or an ether;
- and
- R4C is H, C1-C5 alkyl or C1-C5 alkoxy.
A compound of formula IC, or a pharmaceutically acceptable salt thereof, for use in the treatment of an axonopathy:
- wherein:
- XC is N or C;
- R1C is H, C1-C5 alkyl, C1-C5 alkoxy, or C1-C5 haloalkoxy;
- R2C is C1-C5 alkyl or C1-C5 alkoxy;
- R3C is C1-C10 alkyl, C1-C10 haloalkyl or an ether;
- and
- R4C is H, C1-C5 alkyl or C1-C5 alkoxy.
A method of identifying a SARM1 NADase inhibitor, comprising:
- a. providing a mixture comprising i) a full-length SARM1, ii) NAD+ and iii) a candidate inhibitor, wherein the full-length SARM1 has constitutive NADase activity;
- b. incubating the mixture;
- c. quantifying NAD+ and ADPR in the mixture after the incubating;
- d. determining the molar ratio of NAD+:ADPR;
- and
- e. identifying the candidate inhibitor compound as an NADase inhibitor if the molar ratio is greater than that of a control mixture that does not contain the candidate inhibitor.
A method of identifying a SARM1 NADase inhibitor, comprising:
- a. providing a mixture comprising a solid support to which is bound i) a full-length SARM1 and at least one tag, ii) NAD+, and iii) a candidate inhibitor;
- b. incubating the mixture;
- c. quantifying the NAD+ after the incubating;
- and
- d. identifying the candidate inhibitor compound as an NADase inhibitor if the concentration of NAD+ is greater than that of a control.
A method of identifying a SARM1 NADase inhibitor, comprising:
- a. providing a mixture comprising i) a full-length SARM1, ii) NAD+ and iii) a candidate inhibitor, wherein the full-length SARM1 has constitutive NADase activity;
- b. incubating the mixture;
- c. quantifying NAD+ in the mixture after the incubating;
- and
- d. identifying the candidate inhibitor compound as an NADase inhibitor if the amount of NAD+ is greater than that of a control mixture that does not contain the candidate inhibitor.
A method of identifying a SARM1 NADase inhibitor, comprising:
- a) providing a mixture comprising i) a full-length SARM1 that has constitutive NADase activity, ii) NAD+ and iii) a candidate inhibitor, wherein the full-length SARM1 has constitutive NADase activity;
- b) incubating the mixture;
- c) quantifying NAD+ and at least one NADase cleavage product in the mixture after the incubating;
- and
- d) identifying the candidate inhibitor compound as an NADase inhibitor if the molar ratio of NAD+ to the at least one NADase cleavage product is greater than that of a control mixture that does not contain the candidate inhibitor.
A SARM1 polypeptide comprising at least a functional fragment of a SARM1 N-terminal auto-inhibitory domain, at least a functional fragment of one or more SAM domains, and at least a functional fragment of a SARM1 TIR domain, wherein the SARM1 polypeptide lacks a mitochondrial targeting sequence.
Dependencies are inferred from the claim text.