CASPASE-1 INHIBITION AND USES THEREOF FOR PREVENTION AND TREATMENT OF NEUROLOGICAL CONDITIONSDescribed herein are methods for preventing, delaying the onset or reducing the severity of, preventing or reversing the progression of, or treating a neurological condition (e.g., a neurodegenerative disease (e.g., Alzheimer's disease)) in a subject, based on caspase-1 inhibition. Also described herein are methods for preventing, delaying the onset or reducing the severity of, preventing or reversing the progression of, or treating cognitive impairment in a subject, based on caspase-1 inhibition. Corresponding uses and kits are also described. In an embodiment, the caspase-1 inhibitor is VX-765 or a pharmaceutically acceptable salt thereof.A method of preventing, delaying the onset or reducing the severity of, preventing or reversing the progression of, or treating a neurological condition in a subject, said method comprising administering a caspase-1 inhibitor to the subject.The method of claim 1 , wherein the caspase-1 inhibitor is a compound having Formula I:wherein R1 isR2 and R3 taken together form a ring, wherein said ring is: wherein, in each ring, any hydrogen atom is optionally and independently replaced by R7 and any set of two hydrogen atoms bound to the same atom is optionally and independently replaced by carbonyl;when the ring formed by R2 and R3 isthenR5 is R8C(0)— , andR8 is phenyl, thiophene, or pyridine, wherein each ring is optionally substituted with up to 5 groups independently selected from R9, and wherein at least one position on the phenyl, thiophene, or pyridine is substituted by R10;when the ring formed by R2 and R3 is thenR5 is R8C(0)— , HC(O), R8S02— , R8OC(0), (R8)2NC(0), (R8)(H)NC(0), R8C(0)C(0)— , R8— , (R8)2NC(0)C(0), (R8)(H)NC(0)C(0), or R8OC(0)C(0)— ; andR8 is C1-12aliphatic, C3-10cycloaliphatic, C6-10aryl, 5-10 membered heterocyclyl, 5-10 membered heteroaryl, (C3-10cycloaliphatic)-(C1-12aliphatic)-, (C6-10aryl)-(C1-12aliphatic)-, (5-10 membered heterocyclyl)-(C1-12aliphatic)-, or (5-10 membered heteroaryl)-(C1-12aliphatic)-; or two R8 groups bound to the same atom form together with that atom a 3-10 membered aromatic or nonaromatic ring; wherein any ring is optionally fused to an C6-ioaryl, 5-10 membered heteroaryl, C3-10cycloalkyl, or 5-10 membered heterocyclyl; wherein up to 3 aliphatic carbon atoms may be replaced by a group selected from O, N, NR11 , S, SO, and S02, wherein R8 is substituted with up to 6 substituents independently selected from R12;R4 is H, C1-12aliphatic, C3-10cycloaliphatic, C6-10aryl, 5-10 membered heterocyclyl, 5-10 membered heteroaryl, (C3-10cycloalkyl)-(C1-12aliphatic)-, cycloalkenyl-(C1-12aliphatic)-, (C6-10aryl)- (C1-12aliphatic)-, (5-10 membered heterocyclyl)-(C1-12 aliphatic)-, or (5-10 membered heteroaryl)- (C1-12aliphatic)-, wherein any hydrogen atom is optionally and independently replaced by R12 and any set of two hydrogen atoms bound to the same atom is optionally and independently replaced by carbonyl;R6 is— C(R13)(R14)(R15), C6-10aryl, 5-10 membered heteroaryl, or Cs-ycycloalkyl;R7 is halogen, —OR11, — N02— CN— CF3, — OCFi, — R11, 1 ,2-methylenedioxy, 1 ,2- ethylenedioxy,— N(R11)2,— SR11 ,— SOR11,— S02R11— S02N(R11)2,— S03R11,— C(0)R11 ,— C(0)C(0)R11, — C(0)C(0)OR11, — C(0)C(0)N(R11)2, — C(0)CH2C(0)R11 , — C(S)R11, — C(S)OR11,— C(0)OR11,— OC(0)R11 ,— C(0)N(R11)2,— OC(0)N(R11)2,— C(S)N(R11)2,— (CH2)o- 2NHC(0)R11, — N(R11)N(R11)COR11 , — N(R11)N(R11)C(0)OR11, — N(R11)N(R11)CON(R11)2, — N(R11)S02R11 ,— N(R11)S02N(R11)2,— N(R11)C(0)OR11 ,— N(R11)C(0)R11,— N(R11)C(S)R11 ,— N(R11)C(0)N(R11)2,— N(R11)C(S)N(R11)2— N(COR11)COR11,— N(OR11)R11 ,— C(=NH)N(R11)2,— C(0)N(OR11)R11, — C(=NOR11)R11, — OP(0)(OR11)2, — P(0)(R11)2, — P(0)(OR11)2, or — P(0)(H)(OR11);R9 and R12 are each independently halogen,—OR11 ,— N02,— CN,— CF3,— OCF3,— R11, 1 ,2-methylenedioxy, 1 ,2-ethylenedioxy, — N(R11)2, — SR11, —SOR11, — S02R11 , — S02N(R11)2— SO3R11 , — C(0)R11, — C(0)C(0)R11, — C(0)C(0)OR11, — C(0)C(0)N(R11)2, — C(0)CH2C(0)R11, — C(S)R11, — C(S)OR11 , — C(0)OR11 , — OC(0)R11, — C(0)N(R11)2, — OC(0)N(R11)2, — C(S)N(R1 1)2, — (CH2)0-2NHC(O)R11 , — N(R1 1)N(R11)COR11 , — N(R11)N(R1 1)C(0)OR1 1 , — N(R11)N(R1 1)CON(R11)2, — N(R11)S02R11 , — N(R11)S02N(R11)2, — N(R11)C(0)OR11 ,— N(R1 1)C(0)R11 ,— N(R11)C(S)R1 1 ,— N(R11)C(0)N(R11)2,— N(R1 1)C(S)N(R1 1)2, — N(COR11)COR1 1 , — N(OR11)R11 , — C(=NH)N(R11)2, — C(0)N(OR1 1)R1 1 , — C(=NOR11)R1 1 , — OP(0)(OR11)2,— P(0)(R1 1)2,— P(0)(OR1 1)2, or— P(0)(H)(OR11);R10 is halogen,—OR17,— N02— CN— CF3— OCF3,— R17, or— SR1 1 , wherein R10 has no more than 5 straight-chained atoms;R11 is hydrogen, C1-12aliphatic, C3-10cycloaliphatic, C6-10aryl, 5-10 membered heterocyclyl, 5-10 membered heteroaryl, (C3-10cycloaliphatic)-(C1-12aliphatic)-, (Cs-ioaryl)-(C1-12aliphatic)-, (5-10 membered heterocyclyl)-(C1-12aliphatic)-, or heteroaryl-(C1-12aliphatic)-; wherein any hydrogen atom is optionally and independently replaced by R18 and any set of two hydrogen atoms bound to the same atom is optionally and independently replaced by carbonyl;R13 is H or a Ci-e straight-chained or branched alkyl;R14 is H or a C1-6 straight-chained or branched alkyl;R15 is— CF3,— C3-7cycloalkyl, C6-10aryl, 5-10 membered heteroaryl, heterocycle, or a Ci-6 straight-chained or branched alkyl, wherein each carbon atom of the alkyl is optionally and independently substituted with R16;or R13 and R15 taken together with the carbon atom to which they are attached form a 3- 10 membered cycloaliphatic;R16 is halogen,—OR17,— N02,— CN,— CF3— OCF3,— R17, or— SR17; wherein R17 is Ci-4-aliphatic-;R17 is C1.4-alipha.ic-; andR18 is —OR17, — N02, — CN, — CF3, — OCF3, — R17, 1 ,2-methylenedioxy, 1 ,2- ethylenediox...
카스파제-1 억제 및 신경학적 병태의 예방 및 치료를 위한 이의 용도본원에 기재된 것은 카스파제-1 억제를 기초로 하여 대상체에서, 신경학적 병태 (예를 들어, 신경퇴행성 질환 (예를 들어, 알츠하이머 질환)의 발병을 예방하거나, 지연시키거나, 이의 중증도를 감소시키거나, 이의 진행을 예방하거나, 역전시키거나, 치료하기 위한 방법이다. 또한 본원에 기재된 것은 카스파제-1 억제를 기초로 하여 대상체에서 인지 손상의 발병을 예방하거나, 지연시키거나, 이의 중증도를 감소시키거나, 이의 진행을 예방하거나, 역전시키거나, 치료하기 위한 방법이다. 상응하는 용도 및 키트가 또한 기재된다. 일 구현예에서, 상기 카스파제-1 억제제는 VX-765 또는 이의 약제학적으로 허용되는 염이다.대상체에서 신경학적 병태의 발병을 예방하거나, 지연시키거나, 이의 중증도를 감소시키거나, 이의 진행을 예방하거나, 역전시키거나, 치료하는 방법으로서, 상기 방법이 상기 대상체에게 카스파제-1 억제제를 투여함을 포함하는, 방법.