Compounds and methods useful for stabilizing phenylalanine hydroxylase mutations
AssigneeAgios Pharmaceuticals, Inc.
InventorsSandra King, Zenon Konteatis, Brian C. Shook
Life of this patent
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Abstract
The disclosure relates to compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein, m, R1-R5, R5A, and L are defined herein. These compounds are useful in methods for stabilizing a mutant PAH protein or reducing blood phenylalanine concentration in a subject suffering from phenylketonuria. In some embodiments, the mutant PAH protein contains at least one R408W, R261Q, R243Q, Y414C, L48S, A403V, I65T, R241C, L348V, R408Q, or V388M mutation. In other embodiments, the mutant PAH protein contains at least one R408W, Y414C, I65T, F39L, R408Q, L348V, R261Q, A300S, or L48S mutation.
Claims40
A compound of Formula I:
- or a pharmaceutically acceptable salt thereof, wherein:
- m is 1 or 2;
- R1 is
- E is O, S, or NH;
- x is 0 to 5;
- w is 0 to 4;
- each Ra independently is halo, C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, C1-6alkoxy or C1-6haloalkoxy;
- R2 is optionally substituted C3-8cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
- R3 is H or C1-6alkyl;
- R4 is H or C1-6alkyl;
- or R3 and R4, together with the atom to which they are attached, form a C3-6cycloalkyl;
- R5 is H or D;
- R5A is H or D;
- L is a bond, —C(O)—, —C(O)CH2—, —C(O)CH2CH2—, —C(O)CH2CH2CH2—, —C(O)CF2—, —C(O)CHF—, —C(O)C(CH3)2—, —C(O)CH═CH—,
- or —C(O)NHCH2.
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Dependencies are inferred from the claim text.