US2021116467A1PendingUtilityA1
Diabetes-related biomarkers and treatment of diabetes-related conditions
Est. expiryOct 18, 2035(~9.3 yrs left)· nominal 20-yr term from priority
Inventors:Wei Jia
G16B 25/10G01N 33/92G01N 2800/60G16C 20/30G01N 33/6893G01N 2800/042C07J 9/005G16B 25/00G01N 2800/50A61P 3/10G01N 2800/52C07J 41/0061
69
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Claims
Abstract
The present invention provides biomarkers useful for evaluating the risk that a subject will develop diabetes, monitoring such risk, identifying members of a population at risk of developing diabetes, calculating risk of a subject developing diabetes, advising subjects of risk for developing diabetes, providing diagnostic tests for identifying subjects at risk for developing diabetes or kits there for, and providing diagnostic tests for determining risk of a subject developing diabetes and kits there for. The present invention also provides compounds and methods for treating subjects.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A method of determining the risk of a subject developing diabetes comprising:
a. obtaining a biological sample from the subject; b. measuring the level of each biomarker of a panel in the sample, wherein the panel comprises at least one biomarker listed in FIG. 11 ; c. correlating the measured level with risk of developing diabetes; and d. determining the risk of the subject developing diabetes based on the correlation; and e. optionally, administering a treatment to the subject determined to be likely to develop diabetes.
2 . The method of claim 1 , wherein the step of correlating comprises calculating a score from the measured level of the at least one biomarker.
3 . The method of claim 2 , wherein the score is output from a model wherein the model is executed based on an input of the measured level of each biomarker of the panel.
4 . The method of claim 3 , wherein the step of determining comprises comparing the calculated score to a threshold score, wherein the subject is determined as likely to develop diabetes if the calculated score exceeds the threshold score.
5 . The method of claim 1 , wherein the step of correlating comprises comparing the measured level of each of the at least one biomarker to a respective comparator level.
6 . The method of any of claims 1 - 5 , wherein the panel comprises a panel selected from panels A through BZ listed in FIG. 12A-12C .
7 . The method of any of claims 1 - 5 , wherein the step of measuring comprises measuring by mass-spectroscopy (‘MS’).
8 . The method of claim 7 , wherein the MS comprises one or more of time-of-flight MS, ion trap MS, quadrupole MS, magnetic sector MS, ion cyclotron resonance MS, and electrostatic sector analyzer MS.
9 . The method of any of claims 1 - 5 , wherein the method comprises extracting the at least one biomarker from the sample.
10 . The method claim 9 wherein the extracting comprises filtering the sample to provide a filtrate, and measuring the at least one biomarker in the filtrate.
11 . The method of claim 10 , wherein the method comprises a step of protein precipitation prior to filtering.
12 . The method of any of claims 1 - 5 , wherein the method comprises separating the at least one biomarker from one or more other biomarkers.
13 . The method of claim 12 , wherein the separation step comprises gas chromatography (‘GC’) or liquid chromatography (‘LC’).
14 . The method of claim 13 , wherein the measuring step comprises ultra-performance liquid chromatography-triple quadrupole mass spectrometry (‘UPLC-TQMS’).
15 . The method of claim 14 , wherein the UPLC-TQMS is performed in negative ion mode.
16 . The method of any of claims 1 - 5 , wherein the measuring step comprises enzymatic analysis, chemical analysis, colorimetric analysis, or fluorometric analysis.
17 . The method of any of claims 1 - 5 , wherein the at least one biomarker of FIG. 11 comprises one or more of:
a. Glycohyodeoxycholic acid (‘GHDCA’) or % GHDCA of total bile acids;
b. Glycohyocholic acid (‘GHCA’) or % GHCA of total bile acids;
c. Hyodeoxycholic acid (‘HDCA’) or % HDCA of total bile acids;
d. Hyocholic acid (‘HCA’) or % HCA of total bile acids;
e. Taurohyodeoxycholic acid (‘THDCA’) or % THDCA of total bile acids
f. C16:0/C18:0 ratio;
g. C18:1 n9/C18:0 ratio;
h. C20:3 n6/C20:4;
i. Isoleucine, Leucine, Tyrosine, Valine, and Phenylalanine; and
j. Total triglycerides (‘TG’);
18 . The method of any of claims 1 - 5 , wherein the at least one biomarker of FIG. 11 comprises;
a. one or more or all of the BCAAs of FIG. 11 ;
b. one or both of phenylalanine and tyrosine;
c. one or more or all of the free fatty acids of FIG. 11 ;
d. one or more or all of the bile acids of FIG. 11 ;
e. TG; or
f. a combination of any two or three of a)-e).
19 . The method of any of claims 1 - 5 , wherein the at least one biomarker of FIG. 11 comprises:
a. GHDCA or % GHDCA of total bile acids, THDCA or % THDCA, HDCA or % HDCA of total bile acids, HCA or % HCA of total bile acids, GHCA or % GHCA, and THCA or % THCA;
b. Palmitic acid (C16:0), Stearic acid (C18:0), Oleic acid (C18:1 n9), dihomo-γ-linolenic acid (C20:3 n6), and Arachidonic acid (C20:4 n6);
c. Isoleucine, Leucine, Tyrosine, Valine, and Phenylalanine;
d. TG;
e. a combination of a) and b), a) and c), b) and c), or each of a), b), and c);
f. a combination of (a) and (b), (a) and (c), (a) and (d), (b) and (c), (b) and (d), or (c) and (d);
g. a combination (a), (b), and (c);
h. a combination (a), (b), and (d);
i. a combination (a), (c), and (d); or
j. a combination (b), (c), and (d).
20 . The method of any of claims 1 - 5 , wherein the at least one biomarker of FIG. 11 comprises:
a. one or more of GHDCA or % GHDCA of total bile acids, THDCA or % THDCA, HDCA or % HDCA of total bile acids, HCA or % HCA of total bile acids, GHCA or % GHCA, and THCA or % THCA
b. one or more of Palmitic acid (C16:0), Stearic acid (C18:0), Oleic acid (C18:1 n9), dihomo-γ-linolenic acid (C20:3 n6), and Arachidonic acid (C20:4 n6);
c. one or more of Isoleucine, Leucine, Tyrosine, Valine, and Phenylalanine;
d. TG;
e. a combination of a) and b), a) and c), b) and c), or each of a), b), a
f. a combination of (a) and (b), (a) and (c), (a) and (d), (b) and (c), (b) and (d), or (c) and (d);
g. a combination (a), (b), and (c);
h. a combination (a), (b), and (d);
i. a combination (a), (c), and (d); or
j. a combination (b), (c), and (d).
21 . The method of any of the preceding claims, wherein the sample comprises blood, serum, plasma, urine, saliva, or sweat.
22 . The method of claim 21 , wherein the sample is a serum sample.
23 . The method of any of the preceding claims, wherein the subject is any of:
a. metabolically healthy; b. overweight; c. obese; d. not overweight; e. not obese; f. a) and b), or a) and c), and g. a) and d), or a) and e).
24 . The method of any of the preceding claims, wherein the at least one biomarker of FIG. 11 comprises the ratio of palmitic acid:Stearic acid.
25 . The method of the previous claim, wherein the subject does not exhibit
a. a palmitic acid level of at least about 131.2% compared to a non-diabetic population; b. a stearic acid level of at least about 120% compared to a non-diabetic; population.
26 . The method of any of the preceding claims, wherein the subject is treated to prevent the onset of diabetes, delay the onset of diabetes, or reduce diabetes.
27 . The method of the preceding claim, wherein the treatment is selected from:
a. a very low carbohydrate diet or prescription thereof; b. dietary calorie restriction or prescription thereof; c. metabolic surgery; d. an anti-diabetic agent; e. a treatment that reduces the deviation of the one or more biomarkers relative to a comparator indicative of a likelihood to develop diabetes; f. a physical exercise regimen; and g. a treatment that prevents diabetes, delays the onset of diabetes, or ameliorates diabetes.
28 . The method of claim 27 , wherein the treatment comprises metabolic surgery.
29 . The method of claim 27 , wherein the treatment comprises an anti-diabetic agent selected from an insulin sensitizer, a peroxisome proliferator-activated receptor (‘PPAR’) activator), a bile acid or derivative thereof, a bile acid sequesterant, a DPP-4 inhibitor, a GLP-1, a GLP-1 receptor agonist, a TGR5 agonist, a sulfonylurea, a meglitinide, a Sodium-glucose co-transporter 2 (‘SGLT2’) inhibitor, an alpha-glucosidase inhibitor, a dopamine agonist, and an amylin mimetic.
30 . A method of monitoring diabetes treatment of a subject comprising:
a. obtaining a first biological sample from the subject and a second biological sample from the subject, wherein the first biological sample is obtained from the subject prior to the subject receiving a diabetes treatment and wherein the second biological sample is obtained from the subject following the subject receiving the diabetes treatment; b. measuring the level of at least one biomarker of FIG. 11 in the first sample and the second sample; c. comparing the measured level of the at least one biomarker in the first sample to the measured level of the at least one biomarker in the second sample; d. determining the efficacy of the treatment based on based on a deviation in the measured level of the at least one biomarker in the first sample relative to the measured level of the at least one biomarker in the second sample; and e. optionally, changing or discontinuing the treatment if the efficacy is determined to be below a threshold.
31 . The method of claim 30 , wherein the method is performed according to the features set forth in any of claims 2 - 22 .
32 . A kit for detecting a plurality of biomarkers listed in FIG. 11 , wherein:
a. the kit comprises at least one internal standard, b. the at least one internal standard is:
i. not naturally occurring blood, plasma, or serum;
ii. optionally isotopically labeled;
iii. corresponds to at least one of the biomarkers listed in FIG. 11 .
33 . The kit of claim 32 , wherein the least one internal standard is a plurality of internal standards, wherein collectively, the plurality of internal standards comprise an internal standard corresponding to each of the biomarkers in a panel, wherein the panel comprises a panel selected from panels A-BZ listed in FIG. 12A-12C .
34 . The kit of claim 33 , wherein the plurality of internal standards comprises a steroid acid, a fatty acid, an amino acid, a triglyceride, or a combination thereof, optionally wherein the steroid acid is a bile acid.
35 . The kit of claim 34 , wherein each of the steroid acid, the fatty acid, the amino acid, the triglyceride, or the combination thereof is a stable isotope labeled variant of a respective biomarker of the panel.
36 . The kit of any of any of claims 32 - 35 , further comprising a container, wherein the least one internal standard is provided in the container.
37 . The kit of any of any of claims 32 - 35 , further comprising a filter, wherein the least one internal standard is comprised by the filter.
38 . The kit of any of any of claims 32 - 35 , wherein the least one internal standard is a plurality of internal standards provided as a mixture.
39 . The kit of any of any of claims 32 - 35 , wherein the at least one internal standard is freeze-dried.
40 . The kit of any of any of claims 32 - 35 , wherein the at least one internal standard is configured for GC-MS or LC-MS.
41 . The kit of any of any of claims 32 - 35 , comprising a plurality of containers, wherein each container comprises a portion of said at least one internal standard.
42 . The kit of any of any of claims 32 - 36 , further comprising a filter, wherein the least one internal standard is comprised by the filter.
43 . The kit of any of any of claims 32 - 36 and 42 , wherein the least one internal standard is a plurality of internal standards provided as a mixture.
44 . The kit of any of any of claims 32 - 36 and 42 - 43 , wherein the at least one internal standard is freeze-dried.
45 . The kit of any of any of claims 32 - 36 and 42 - 44 , wherein the at least one internal standard is configured for GC-MS or LC-MS.
46 . The kit of any of any of claims 32 - 36 and 42 - 45 , comprising a plurality of containers, wherein each container comprises a portion of said at least one internal standard.
47 . A method of predicting diabetes risk or monitoring diabetes treatment comprising:
a. providing a kit of any of claims 32 - 35 ; and b. performing the method of any of the previous method claims, wherein the sample is mixed with the at least one internal standard prior to the measuring step.
48 . The method of claim 47 , wherein the wherein the sample is mixed with the at least one internal standard prior to a step of extracting the biomarkers from the sample.
49 . The method of claim 48 , wherein the kit comprises a filter and the a step of extracting comprises filtering the sample using the filter.
50 . A method of predicting diabetes risk or monitoring diabetes treatment comprising:
a. providing a kit of any of claims 42 - 46 ; and b. performing the method of any of the previous method claims, wherein the sample is mixed with the at least one internal standard prior to the measuring step.
51 . The method of claim 50 , wherein the wherein the sample is mixed with the at least one internal standard prior to a step of extracting the biomarkers from the sample.
52 . The method of claim 51 , wherein the kit comprises a filter and the a step of extracting comprises filtering the sample using the filter.
53 . The method of any of the preceding method claims, wherein the measuring step comprises measuring by mass-spectroscopy (‘MS’).
54 . The method of the previous claim, wherein the MS comprises one or more of time-of-flight MS, ion trap MS, quadrupole MS, magnetic sector MS, ion cyclotron resonance MS, and electrostatic sector analyzer MS.
55 . The method of any of the preceding method claims, wherein the method comprises extracting the at least one biomarker from the sample.
56 . The method of the previous claim, wherein the extracting comprises filtering the sample to provide a filtrate, and measuring the at least one biomarker in the filtrate.
57 . The method of the previous claim, wherein the method comprises a step of protein precipitation prior to filtering.
58 . The method of any of the preceding method claims, wherein the method comprises separating the at least one biomarker from one or more other biomarkers.
59 . The method of the previous claim, wherein the separation step comprises gas chromatography (‘GC’) or liquid chromatography (‘LC’).
60 . The method of the previous claim, wherein the measuring step comprises ultra-performance liquid chromatography-triple quadrupole mass spectrometry (‘UPLC-TQMS’).
61 . The method of the previous claim, wherein the UPLC-TQMS is performed in negative ion mode.
62 . The method of any of the preceding method claims, wherein the measuring step comprises enzymatic analysis, chemical analysis, colorimetric analysis, or fluorometric analysis.
63 . The method of any of the preceding method claims, wherein the at least one biomarker of FIG. 11 comprises one or more of:
a. Glycohyodeoxycholic acid (‘GHDCA’) or % GHDCA of total bile acids;
b. Hyodeoxycholic acid (‘HDCA’) or % HDCA of total bile acids;
c. Hyocholic acid (‘HCA’) or % HCA of total bile acids;
d. Taurohyodeoxycholic acid (‘THDCA’) or % THDCA of total bile acids
e. C16:0/C18:0 ratio;
f. C18:1 n9/C18:0 ratio;
g. C20:3 n6/C20:4;
h. Isoleucine, Leucine, Tyrosine, Valine, and Phenylalanine; and
i. Total triglycerides (‘TG’).
64 . The method of any of the preceding method claims, wherein the at least one biomarker of FIG. 11 comprises:
a. GHDCA or % GHDCA of total bile acids, THDCA or % THDCA, HDCA or % HDCA of total bile acids, HCA or % HCA of total bile acids, GHCA or % GHCA, and THCA or % THCA
b. Palmitic acid (C16:0), Stearic acid (C18:0), Oleic acid (C18:1 n9), dihomo-γ-linolenic acid (C20:3 n6), and Arachidonic acid (C20:4 n6);
c. Isoleucine, Leucine, Tyrosine, Valine, and Phenylalanine;
d. TG
e. a combination of a) and b), a) and c), b) and c), or each of a), b), a
f. a combination of (a) and (b), (a) and (c), (a) and (d), (b) and (c), (b) and (d), or (c) and (d);
g. a combination (a), (b), and (c);
h. a combination (a), (b), and (d);
i. a combination (a), (c), and (d); or
j. a combination (b), (c), and (d).
65 . The method of any of the preceding method claims, wherein the sample comprises blood, serum, plasma, urine, saliva, or sweat.
66 . The method of any of the preceding method claims, wherein the subject is any of:
a. metabolically healthy; b. overweight; c. obese; d. not overweight; e. not obese; f. a) and b), or a) and c), and g. a) and d), or a) and e).
67 . The method of any of the preceding method claims, wherein the treatment is selected from:
a. a very low carbohydrate diet or prescription thereof; b. dietary calorie restriction or prescription thereof; c. metabolic surgery; d. an anti-diabetic agent; and e. a treatment that reduces the deviation of the one or more biomarkers relative to a comparator indicative of a likelihood to develop diabetes.
68 . The method of the previous claim, wherein the treatment comprises metabolic surgery.
69 . The method of claim 67 , wherein the treatment comprises an anti-diabetic agent selected from an insulin sensitizer, a peroxisome proliferator-activated receptor (‘PPAR’) activator), a bile acid or derivative thereof, a bile acid sequesterant, a DPP-4 inhibitor, a GLP-1, a GLP-1 receptor agonist, a TGR5 agonist, a sulfonylurea, a meglitinide, a Sodium-glucose co-transporter 2 (‘SGLT2’) inhibitor, an alpha-glucosidase inhibitor, a dopamine agonist, and an amylin mimetic.
70 . A compound of Formula I or a pharmaceutically acceptable salt or conjugate thereof,
wherein:
R1 is selected from α-OH and β-O(CH 2 )nOH wherein n=1-10;
R2 is selected from α-OH, α-(CH 2 )pCH 3 wherein p=0-6, and —O(CH 2 )qCH 3 wherein q=0-6;
R3 is selected from α-OH and —H;
R4 is selected from —H and —(CH 2 )xCH 3 wherein x=0-6; and
R5 is selected from —OH, —NH(CH 2 )COOH, —NH(CH 2 ) 2 SO3H, —O(CH 2 )yCH 3 wherein y=0-1, or —NH(CH 2 )zCO 2 Et wherein z=1-10.
71 . The compound of claim 70 , wherein:
R1 is β-O(CH 2 )nOH wherein n=1-10; R2 is selected from α-(CH 2 )pCH 3 wherein p=0-6, or —O(CH 2 )qCH 3 wherein q=0-6; R3 is α-OH; R4 is —(CH 2 )xCH 3 wherein x=0-6; or R5 is selected from —O(CH 2 )yCH 3 wherein y=0-1, or —NH(CH 2 )zCO 2 Et wherein z=1-10.
72 . The compound of claim 71 , wherein:
R1 is β-O(CH 2 )nOH wherein n=1-10; R2 is α-(CH 2 )pCH 3 wherein p=0-6, or —O(CH 2 )qCH 3 wherein q=0-6; R3 is α-OH; R4 is —(CH 2 )xCH 3 wherein x=0-6; and R5 is —O(CH 2 )yCH 3 wherein y=0-1, or —NH(CH 2 )zCO 2 Et wherein z=1-10.
73 . The compound of claim 70 or claim 71 , wherein:
R1 is β-O(CH 2 )nOH wherein n=1-10; and
R2 is α-(CH 2 )pCH 3 wherein p=0-6, or —O(CH 2 )qCH 3 wherein q=0-6.
74 . The compound of claim 70 or claim 71 , wherein:
R1 is β-O(CH 2 )nOH wherein n=1-10; and
R3 is α-OH.
75 . The compound of claim 70 or claim 71 , wherein:
R1 is β-O(CH 2 )nOH wherein n=1-10; and
R4 is —(CH 2 )xCH 3 wherein x=0-6.
76 . The compound of claim 70 or claim 71 , wherein:
R1 is β-O(CH 2 )nOH wherein n=1-10; and
R5 is O(CH 2 )yCH 3 wherein y=0-1, or NH(CH 2 )zCO 2 Et wherein z=1-10.
77 . The compound of claim 70 or claim 71 , wherein:
R2 is α-(CH 2 )pCH 3 wherein p=0-6, or —O(CH 2 )qCH 3 wherein q=0-6; and
R3 is α-OH.
78 . The compound of claim 70 or claim 71 , wherein:
R2 is α-(CH 2 )pCH 3 wherein p=0-6, or —O(CH 2 )qCH 3 wherein q=0-6; and
R4 is —(CH 2 )xCH 3 wherein x=0-6.
79 . The compound of claim 70 or claim 71 , wherein:
R2 is α-(CH 2 )pCH 3 wherein p=0-6, or —O(CH 2 )qCH 3 wherein q=0-6; and
R5 is O(CH 2 )yCH 3 wherein y=0-1, or NH(CH 2 )zCO 2 Et wherein z=1-10.
80 . The compound of claim 70 or claim 71 , wherein:
R3 is α-OH; and
R4 is —(CH 2 )xCH 3 wherein x=0-6.
81 . The compound of claim 70 or claim 71 , wherein:
R3 is α-OH; and
R5 is O(CH 2 )yCH 3 wherein y=0-1, or NH(CH 2 )zCO 2 Et wherein z=1-10.
82 . The compound of claim 70 or claim 71 , wherein:
R4 is —(CH 2 )xCH 3 wherein x=0-6; and
R5 is O(CH 2 )yCH 3 wherein y=0-1, or NH(CH 2 )zCO 2 Et wherein z=1-10.
83 . The compound of claim 70 or claim 71 , wherein:
R1 is β-O(CH 2 )nOH wherein n=1-10; and
R2 is α-(CH 2 )pCH 3 wherein p=0-6, or —O(CH 2 )qCH 3 wherein q=0-6; and
R3 is α-OH.
84 . The compound of claim 70 or claim 71 , wherein:
R2 is α-(CH 2 )pCH 3 wherein p=0-6, or —O(CH 2 )qCH 3 wherein q=0-6;
R3 is α-OH; and
R4 is —(CH 2 )xCH 3 wherein x=0-6.
85 . The compound of claim 70 or claim 71 , wherein:
R3 is α-OH;
R4 is —(CH 2 )xCH 3 wherein x=0-6; and
R5 is O(CH 2 )yCH 3 wherein y=0-1, or NH(CH 2 )zCO 2 Et wherein z=1-10.
86 . The compound of claim 70 or claim 71 , wherein:
R1 is β-O(CH 2 )nOH wherein n=1-10; and
R3 is α-OH; and
R4 is —(CH 2 )xCH 3 wherein x=0-6.
87 . The compound of claim 70 or claim 71 , wherein:
R1 is β-O(CH 2 )nOH wherein n=1-10; and
R3 is α-OH; and
R5 is O(CH 2 )yCH 3 wherein y=0-1, or NH(CH 2 )zCO 2 Et wherein z=1-10.
88 . The compound of claim 70 or claim 71 , wherein:
R1 is β-O(CH 2 )nOH wherein n=1-10; and
R4 is —(CH 2 )xCH 3 wherein x=0-6; and
R5 is O(CH 2 )yCH 3 wherein y=0-1, or NH(CH 2 )zCO 2 Et wherein z=1-10.
89 . The compound of claim 70 or claim 71 , wherein:
R2 is α-(CH 2 )pCH 3 wherein p=0-6, or —O(CH 2 )qCH 3 wherein q=0-6;
R4 is —(CH 2 )xCH 3 wherein x=0-6; and
R5 is O(CH 2 )yCH 3 wherein y=0-1, or NH(CH 2 )zCO 2 Et wherein z=1-10.
90 . The compound of claim 70 or claim 71 , wherein:
R1 is β-O(CH 2 )nOH wherein n=1-10; and
R2 is α-(CH 2 )pCH 3 wherein p=0-6, or —O(CH 2 )qCH 3 wherein q=0-6;
R3 is α-OH; and
R4 is —(CH 2 )xCH 3 wherein x=0-6.
91 . The compound of claim 70 or claim 71 , wherein:
R1 is β-O(CH 2 )nOH wherein n=1-10;
R3 is α-OH;
R4 is —(CH 2 )xCH 3 wherein x=0-6; and
R5 is O(CH 2 )yCH 3 wherein y=0-1, or NH(CH 2 )zCO 2 Et wherein z=1-10.
92 . The compound of claim 70 or claim 71 , wherein:
R1 is β-O(CH 2 )nOH wherein n=1-10; and
R2 is α-(CH 2 )pCH 3 wherein p=0-6, or —O(CH 2 )qCH 3 wherein q=0-6;
R3 is α-OH; and
R5 is O(CH 2 )yCH 3 wherein y=0-1, or NH(CH 2 )zCO 2 Et wherein z=1-10.
93 . The compound of claim 70 or claim 71 , wherein:
R1 is β-O(CH 2 )nOH wherein n=1-10; and
R2 is α-(CH 2 )pCH 3 wherein p=0-6, or —O(CH 2 )qCH 3 wherein q=0-6;
R3 is α-OH;
R4 is —(CH 2 )xCH 3 wherein x=0-6; or
R5 is O(CH 2 )yCH 3 wherein y=0-1, or NH(CH 2 )zCO 2 Et wherein z=1-10.
94 . The compound of claim 70 or claim 71 , wherein:
R2 is α-(CH 2 )pCH 3 wherein p=0-6, or —O(CH 2 )qCH 3 wherein q=0-6;
R3 is α-OH;
R4 is —(CH 2 )xCH 3 wherein x=0-6; or
R5 is O(CH 2 )yCH 3 wherein y=0-1, or NH(CH 2 )zCO 2 Et wherein z=1-10
95 . The compound of any of claims 70 - 94 , wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
96 . The compound of any of claims 70 - 94 , wherein p is 0, 1, 2, 3, 4, 5 or 6.
97 . The compound of any of claims 70 - 94 , wherein q is 0, 1, 2, 3, 4, 5 or 6.
98 . The compound of any of claims 70 - 94 , wherein x is 0, 1, 2, 3, 4, 5 or 6.
99 . The compound of any of claims 70 - 94 , wherein z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
100 . A method of treating of preventing the onset of diabetes, delaying the onset of diabetes, or ameliorating diabetes in a subject comprising administering to the subject a compound of any of claims 70 - 99 .Cited by (0)
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