Claudin inhibitors and methods of use thereof
AssigneesThe University of Chicago, The Board of Trustees of the University of Illinois
InventorsChristopher R. Weber, Le Shen, Fatemeh Khalili-Araghi
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Abstract
Provided is a method of treating a disorder mediated by claudin-2 and/or claudin-15, particularly an intestinal disorder, such as colitis or enteritis. The method comprises administering to the subject an effective amount of a compound of formula (I), formula (II), or otherwise as described herein or a pharmaceutically acceptable salt thereof. In another aspect, also provided are compounds of formula (Ia) and pharmaceutically acceptable salts thereof.
Claims40
A method of treating a disorder mediated by claudin-2 and/or claudin-15 in a subject comprising administering to the subject an effective amount of a compound of formula (I)
- wherein
- R5 and R6 are the same and are selected from
- and —C(NHR13)═NR14;
- wherein
- R9 and R11 are the same or different and each is a bond, —CH2—, —CH2CH2—, or —NH—;
- R10 and R12 are the same or different and each is hydrogen, alkyl, or hydroxy;
- and
- R13 and R14 are the same or different and each is alkyl;
- R7 and R8 are the same or different and each is selected from hydrogen, alkyl, halo, nitro, amino, hydroxy, alkoxy, alkylthio, amido, alkylamido, dialkylamido, phenylamido, carboxylate, —R16—C(O)NH-Ph-R5, and R5, wherein R16 is a bond or —NH—;
- and
- Z is selected from
- wherein
- X1 and X2 are the same or different and each is O or S;
- R1 and R2 are the same or different and each is —NH— or a bond;
- R3 and R4 are the same or different and each is —NH—, —CH═CH—, —CH2CH2—, —NHC(O)—, —NHC(O)CH2NHC(O)NH—, or a bond;
- provided that R1 and R3 are not both bonds and R2 and R4 are not both bonds;
- and
- LINKER is selected from
- (i) —(CH2)n— that is optionally substituted with a hydroxy, wherein n is an integer of 1-12,
- (ii) —O(CH2)mO— that is optionally substituted, wherein m is an integer of 3-6,
- (iii) —CH═CH—,
- wherein each R15 is the same or different and is selected from alkyl, halo, nitro, amino, hydroxy, alkoxy, alkylthio, amido, alkylamido, dialkylamido, phenylamido, carboxylate, —R16—C(O)NH-Ph-R5, and R5, wherein R16 is a bond or —NH—, and p is 0 or an integer of 1-2,
- wherein R17 is selected from a bond, —CH═CH—, —N═N—, —CH2—, —NHC(O)—, —C(O)NH—, —NHC(O)NH—, —NHC(O)—(CH2)1-4—C(O)NH—, —NHC(O)NH—(CH2)1-4—NHC(O)NH—, —NHC(O)-Ph-C(O)NH—, and —NHC(O)NH-Ph-NHC(O)NH—, and each R18 is the same or different and each is hydrogen, alkyl, alkoxy, 1,4-dihydroimidazolyl, or —R16—C(O)NH-Ph-R5,
- and (xi) a bond,
- and
- wherein X1 is O or S;
- or a pharmaceutically acceptable salt thereof to the subject.
A compound that is a 1,3- or 1,4-substituted phenyl bridged compound of formula (Ia)
- wherein
- X1 and X2 are the same or different and each is O or S;
- one of R5 and R5′ is
- and the other is hydrogen;
- one of R6 and R6′ is
- and the other is hydrogen;
- wherein R5 and R6 are the same and R5′ and R6′ are the same;
- R10 is hydrogen or alkyl;
- R15A and R15B are the same or different and each is selected from hydrogen, alkyl, alkoxy, amino, alkylamido, 1,4-dihydroimidazolyl, and guanidinyl, or a pharmaceutically acceptable salt thereof.
A method of treating a disorder mediated by inhibiting claudin-2 and/or claudin-15 in a subject comprising administering to the subject an effective amount of a compound selected from
A method of treating a disorder mediated by claudin-2 and/or claudin-15 in a subject comprising administering to the subject an effective amount of a compound of formula (II)
- wherein
- X3 and X4 are the same or different and each is O, S, or NH;
- R5 and R6 are the same and are selected from
- and —C(NHR13)═NR14;
- wherein
- R9 and R11 are the same or different and each is a bond, —CH2—, —CH2CH2—, or —NH—;
- R10 and R12 are the same or different and each is hydrogen, alkyl, or hydroxy;
- and
- R13 and R14 are the same or different and each is hydrogen or alkyl;
- R7, R8, R7′, and R8′ are the same or different and each is independently selected from hydrogen, alkyl, halo, nitro, amino, hydroxy, alkoxy, alkylthio, amido, alkylamido, dialkylamido, phenylamido, carboxylate, —R16—C(O)NH-Ph-R5, and R5, wherein each R16 independently is a bond or —NH—;
- and
- Y is
- wherein
- LINKER is selected from
- (a) —CR21═CR22—,
- (b) —CR212CR222—, and
- wherein each R15, R21, and R22 is the same or different and is independently selected from hydrogen, alkyl, halo, nitro, amino, hydroxy, alkoxy, alkylthio, amido, alkylamido, dialkylamido, phenylamido, carboxylate, —R16—C(O)NH-Ph-R5, and R5, and each p independently is 0 or an integer of 1-2;
- and
- each of R19 and R20 is independently selected from
- (i) a bond,
- (ii) —CR21═CR22—,
- (iii) —CR212CR222—, and
- or a pharmaceutically acceptable salt thereof to the subject.
Dependencies are inferred from the claim text.