METHODS FOR DELAYING OR PREVENTING THE ONSET OF TYPE 1 DIABETES
Described herein are methods for preventing or delaying the onset of Type 1 Diabetes, or inhibiting the maturation of anti-insulin B cells, in an individual in need thereof. The methods include administering to an individual in need thereof ibrutinib, alone or in combination with other Type 1 Diabetes treatments.
1 . A method for preventing or delaying the onset of type 1 diabetes in an individual in need thereof comprising administering to the individual in need thereof a composition comprising a therapeutically-effective amount of a compound of Formula A:
wherein
A is independently selected from N or CR 5 ;
R 1 is H, L 2 -(substituted or unsubstituted alkyl), L 2 -(substituted or unsubstituted cycloalkyl), L 2 -(substituted or unsubstituted alkenyl), L 2 -(substituted or unsubstituted cycloalkenyl), L 2 -(substituted or unsubstituted heterocycle), L 2 -(substituted or unsubstituted heteroaryl), or L 2 -(substituted or unsubstituted aryl), where L 2 is a bond, O, S, —S(═O), —S(═O) 2 , C(═O), -(substituted or unsubstituted C 1 -C 6 alkyl), or -(substituted or unsubstituted C 2 -C 6 alkenyl);
R 2 and R 3 are independently selected from H, lower alkyl and substituted lower alkyl;
R 4 is L 3 -X-L 4 -G, wherein,
L 3 is optional, and when present is a bond, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted alkynyl;
X is optional, and when present is a bond, O, —C(═O), S, —S(═O), —S(═O) 2 , —NH, —NR 9 , —NHC(O), —C(O)NH, —NR 9 C(O), —C(O)NR 9 , —S(═O) 2 NH, —NHS(═O) 2 , —S(═O) 2 NR 9 —, —NR 9 S(═O) 2 , —OC(O)NH—, —NHC(O)O—, —OC(O)NR 9 —, —NR 9 C(O)O—, —CH═NO—, —ON═CH—, —NR 10 C(O)NR 10 —, heteroaryl, aryl, —NR 10 C(═NR 11 )NR 10 —, —NR 10 C(═NR 11 )—, —C(═NR 11 )NR 10 —, —OC(═NR 11 )—, or —C(═NR 11 )O—;
L 4 is optional, and when present is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle;
or L 3 , X and L 4 taken together form a nitrogen containing heterocyclic ring;
G is
wherein,
R 6 , R 7 and R 8 are independently selected from among H, lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, and substituted or unsubstituted lower heterocycloalkyl;
R 5 is H, halogen, -L 6 -(substituted or unsubstituted C 1 -C 3 alkyl), -L 6 -(substituted or unsubstituted C 2 -C 4 alkenyl), -L 6 -(substituted or unsubstituted heteroaryl), or -L 6 -(substituted or unsubstituted aryl), wherein L 6 is a bond, O, S, —S(═O), S(═O) 2 , NH, C(O), —NHC(O)O, —OC(O)NH, —NHC(O), or —C(O)NH;
each R 9 is independently selected from among H, substituted or unsubstituted lower alkyl, and substituted or unsubstituted lower cycloalkyl;
each R 10 is independently H, substituted or unsubstituted lower alkyl, or substituted or unsubstituted lower cycloalkyl; or
two R 10 groups can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring; or
R 10 and R 11 can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring; or
each R 11 is independently selected from H or alkyl; and
pharmaceutically active metabolites, pharmaceutically acceptable solvates,
pharmaceutically acceptable salts, or pharmaceutically acceptable prodrugs thereof.
2 . The method of claim 1 , wherein the compound of Formula A is (R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one
3 . The method of claim 1 , wherein the method prevents the onset of Type 1 Diabetes or delays the onset of Type 1 Diabetes.
4 . The method of claim 1 , wherein the number of anti-insulin B cells in the individual is reduced.
5 . The method of claim 1 , wherein the individual presents with active autoimmunity to at least two of insulin, GAD65, IA-2, and Znt8.
6 . The method of claim 1 , wherein the individual presents with an elevated level of A1C.
7 . The method of claim 1 , wherein the individual presents with impaired fasting glycemia.
8 . The method of claim 8 , wherein the individual presents with fasting plasma glucose level from 5.6 mmol/L (100 mg/dL) to 6.9 mmol/L (125 mg/dL), or from 6.1 mmol/L (100 mg/dL) to 6.9 mmol/L (125 mg/dL).
9 . The method of claim 1 , wherein the individual presents with impaired glucose tolerance.
10 . The method of claim 1 , further comprising co-administering an additional therapeutic agent.
11 . A method for preventing or delaying the onset of type 1 diabetes in an individual in need thereof comprising administering to the individual in need thereof a composition comprising a therapeutically-effective amount of (R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-dlpyrimidin-1-yl]piperidin-1-yl)prop-2-en-1-one
12 . A method for inhibiting the maturation of anti-insulin B cells in an individual in need thereof comprising administering to the individual in need thereof a composition comprising a therapeutically-effective amount of a compound of Formula A:
wherein
A is independently selected from N or CR 5 ;
R 1 is H, L 2 -(substituted or unsubstituted alkyl), L 2 -(substituted or unsubstituted cycloalkyl), L 2 -(substituted or unsubstituted alkenyl), L 2 -(substituted or unsubstituted cycloalkenyl), L 2 -(substituted or unsubstituted heterocycle), L 2 -(substituted or unsubstituted heteroaryl), or L 2 -(substituted or unsubstituted aryl), where L 2 is a bond, O, S, —S(═O), —S(═O) 2 , C(═O), -(substituted or unsubstituted C 1 -C 6 alkyl), or -(substituted or unsubstituted C 2 -C 6 alkenyl);
R 2 and R 3 are independently selected from H, lower alkyl and substituted lower alkyl;
R 4 is L 3 -X-L 4 -G, wherein,
L 3 is optional, and when present is a bond, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted alkynyl;
X is optional, and when present is a bond, O, —C(═O), S, —S(═O), —S(═O) 2 , —NH, —NR 9 , —NHC(O), —C(O)NH, —NR 9 C(O), —C(O)NR 9 , —S(═O) 2 NH, —NHS(═O) 2 , —S(═O) 2 NR 9 —, —NR 9 S(═O) 2 , —OC(O)NH—, —NHC(O)O—, —OC(O)NR 9 —, —NR 9 C(O)O—, —CH═NO—, —ON═CH—, —NR 10 C(O)NR 10 —, heteroaryl, aryl, —NR 10 C(═NR 11 )NR 10 —, —NR 10 C(═NR 11 )—, —C(═NR 11 )NR 10 —, —OC(═NR 11 )—, or —C(═NR 11 )O—;
L 4 is optional, and when present is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle;
or L 3 , X and L 4 taken together form a nitrogen containing heterocyclic ring;
G is
wherein,
R 6 , R 7 and R 8 are independently selected from among H, lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, and substituted or unsubstituted lower heterocycloalkyl;
R 5 is H, halogen, -L 6 -(substituted or unsubstituted C 1 -C 3 alkyl), -L 6 -(substituted or unsubstituted C 2 -C 4 alkenyl), -L 6 -(substituted or unsubstituted heteroaryl), or -L 6 -(substituted or unsubstituted aryl), wherein L 6 is a bond, O, S, —S(═O), S(═O) 2 , NH, C(O), —NHC(O)O, —OC(O)NH, —NHC(O), or —C(O)NH;
each R 9 is independently selected from among H, substituted or unsubstituted lower alkyl, and substituted or unsubstituted lower cycloalkyl;
each R 10 is independently H, substituted or unsubstituted lower alkyl, or substituted or unsubstituted lower cycloalkyl; or
two R 10 groups can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring; or
R 10 and R 11 can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring; or
each R 11 is independently selected from H or alkyl; and
pharmaceutically active metabolites, pharmaceutically acceptable solvates,
pharmaceutically acceptable salts, or pharmaceutically acceptable prodrugs thereof.
13 . The method of claim 12 , wherein the compound of Formula A is (R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one
14 . The method of claim 12 , wherein the number of anti-insulin B cells in the individual is reduced.
15 . The method of claim 12 , wherein the method prevents the onset of Type 1 Diabetes or delays the onset of Type 1 Diabetes.
16 . The method of claim 12 , wherein the individual presents with active autoimmunity to at least two of insulin, GAD65, IA-2, and Znt8.
17 . The method of claim 12 , wherein the individual presents with an elevated level of A1C.
18 . The method of claim 12 , wherein the individual presents with impaired fasting glycemia.
19 . The method of claim 18 , wherein the individual presents with fasting plasma glucose level from 5.6 mmol/L (100 mg/dL) to 6.9 mmol/L (125 mg/dL), or from 6.1 mmol/L (100 mg/dL) to 6.9 mmol/L (125 mg/dL).
20 . The method of claim 12 , wherein the individual presents with impaired glucose tolerance.