Granted Patent B2

US 8,217,025 · App. 11/942,664 · Granted Jul 10, 2012

Abstract

Claims (34)

1. A method to identify a compound with a potential to treat or ameliorate a metabolic disorder in a mammal, comprising selecting a compound that

(i) does not activate one, two or three of PPAR-α, PPAR-γ and PPAR-δ in human or mammalian cells in vitro by more than about 30% when compared to suitable negative control human or mammalian cells in vitro;

(ii) inhibits or decreases the transcriptional activity or level of NF-κB by about 20-80% in human or mammalian cells in vitro when compared to suitable negative control human or mammalian cells in vitro;

(iii) when compared to a suitable negative control or normal control, (a) decreases the degree of hyperglycemia, (b) slows the progression of hyperglycemia, (c) delays the onset of hyperglycemia, (d) decreases the rate of macular degeneration, (e) delays the onset of macular degeneration, (f) decreases the occurrence or incidence of vascular ulcers, (g) decreases the severity of vascular ulcers, (h) increases insulin sensitivity, (i) decreases glucose intolerance, (j) slows the progression or rate of loss of pancreatic β-islet cell numbers or their capacity to secrete insulin, (k) increases pancreatic β-islet cell numbers or their capacity to secrete insulin, (l) slows the rate of weight increase in db/db mice or mice with diet induced obesity, (m) decreases elevated levels of triglycerides, (n) decreases elevated levels total blood or serum cholesterol, (o) decreases normal or elevated levels of LDL, VLDL, apoB-100 or apoB-48 in blood or serum, (p) increases normal or low levels of HDL or apoA1 in blood or serum, (q) decreases or normalizes an elevated level of a phase reactive protein, optionally C reactive protein or fibrinogen in blood or serum, (r) decreases or normalizes hemoglobin A 1C , (s) decreases or normalizes fasting blood glucose levels, (t) normalizes serum or blood glucose in an oral glucose tolerance test, (u) normalizes serum or blood glucose in a 2 hour post prandial glucose test or (v) increases whole body or tissue glucose disposal or uptake in a human or another mammal in vivo, for 1, 2 or 3 of the foregoing;

(iv) optionally, does not activate one or more of a glucocorticoid receptor, an androgen receptor an estrogen receptor-α, estrogen receptor-β or a biologically active variant of any of these biomolecules in human or mammalian cells in vitro by more than about 30% when compared to suitable negative control human or mammalian cells in vitro; and

(v) optionally inhibits the level or activity of phosphoenolpyruvate carboxykinase (PEPCK) or a 11β-hydroxysteroid dehydrogenase (11β-HSD), optionally 11β-HSD type 1 or 11β-HSD type 2 or the level of a mRNA that encodes PEPCK or a 11β-HSD, in hepatocytes or liver-derived cells in vitro or in liver cells or tissue obtained from liver cells or tissue in vivo; wherein the compound with a potential to treat or ameliorate the metabolic disorder in a mammal is identified and optionally recorded as such in a written or a readable electronic medium.

2. The method of claim 1 wherein the mammal is a rodent, an obese rodent, a human or an obese human.

3. The method of claim 2 wherein the metabolic disorder is type II diabetes, hyperglycemia, elevated nonesterified fatty acids or insulin resistance.

4. The method of claim 3 wherein the compound is selected from formula 1 compounds having the structure

wherein, the dotted lines are optional double bonds or if no double bond is present at the 4-5 or 5-6 positions, then hydrogen is present in the α- or β-configuration;

one R 1 is —H or a carbon-linked moiety such as optionally substituted alkyl and the other R 1 is an oxygen-linked moiety, a sulfur-linked moiety or a nitrogen-linked moiety, or both R 1 together are ═O, ═NOH or ═NO—C 1-6 alkyl;

one R 2 is —H or a carbon-linked moiety such as optionally substituted alkyl and the other R 2 is —H, an oxygen-linked moiety, a sulfur-linked moiety or a nitrogen-linked moiety, or both R 2 together are ═O;

one R 3 is —H or a carbon-linked moiety such as optionally substituted alkyl and the other R 3 is —H, an oxygen-linked moiety, a sulfur-linked moiety or a nitrogen-linked moiety;

one R 4 is —H or a carbon-linked moiety such as optionally substituted alkyl and the other R 4 is an oxygen-linked moiety, a sulfur-linked moiety or a nitrogen-linked moiety, or both R 4 together are ═O, ═NOH or ═NO—C 1-6 alkyl;

one R 5 is —H or a carbon-linked moiety such as optionally substituted alkyl and the other R 5 is —H, an oxygen-linked moiety, a sulfur-linked moiety or a nitrogen-linked

moiety, provided that if a double bond is present at the 4-5 position, then R 5 is —H, an oxygen-linked moiety, a sulfur-linked moiety or a nitrogen-linked moiety;

R 6 is —H or C 1-6 optionally substituted alkyl, wherein R 6 optionally is —CH 3 ; and

R 7 is —H or C 1-6 optionally substituted alkyl, wherein R 7 optionally is —CH 3 , —CH 2 OH or —C 2 H 5 ;

R 8 is —CH 2 —, or —C(R 10 ) 2 — where R 10 independently or together are —H, ═O, a carbon-linked moiety such as optionally substituted alkyl, an oxygen-linked moiety, optionally —OH or an ester or ether optionally selected from —OC(O)—CH 3 , —OC(O)—C 2 H 5 , —OCH 3 and —OC 2 H 5 in the α- or β-configuration or R 8 is a sulfur-linked moiety or a nitrogen-linked moiety optionally selected from —SH, —SC(O)—CH 3 , —SC(O)—O 2 H 5 , —SCH 3 and —SC 2 H 5 in the α- or β-configuration; and

R 9 is —CH 2 —, or —C(R 10 ) 2 — where R 10 independently or together are —H, halogen, ═O, a carbon-linked moiety such as optionally substituted alkyl, an oxygen-linked moiety, optionally —OH or an ester or ether optionally selected from —OC(O)—CH 3 , —OC(O)—C 2 H 5 , —OCH 3 and —OC 2 H 5 in the α- or β-configuration, or R 8 is a sulfur-linked moiety or a nitrogen-linked moiety optionally selected from —SH, —SC(O)—CH 3 , —SC(O)—C 2 H 5 , —SCH 3 and —SC 2 H 5 in the α- or β-configuration.

5. The method of claim 4 wherein,

the oxygen-linked moiety is —OH, an ester, phosphate, a phosphoester, sulfate, a sulfate ester, amino acid, a peptide, an ether, a carbonate, a carbamate, or a polymer, any of which are in the α-configuration or the β-configuration;

the sulfur-linked moiety is —SH, a thioester or a thioether, any of which are in the α-configuration or the β-configuration;

the nitrogen-linked moiety is —NH 2 , an amino acid, a peptide, a carbamate, an amide, monosubstituted amine or a disubstituted amine, any of which are in the α-configuration or the β-configuration, or the nitrogen-linked moiety is ═NOH or ═NO—C 1-6 alkyl, where the amine substitution(s) optionally are optionally substituted alkyl and provided that there is 0 or one ═NOH or ═NO—C 1-6 alkyl moieties present; and

the carbon-linked moiety is optionally substituted alkyl, acyl or thioacyl optionally selected from the group consisting of ═CH 2 , ═CHOH, —CH 3 , —CF 3 , —C 2 H 5 , —C 2 F 5 , —CH═CH 2 , —CCH, —CCOH, —C(O)CH 3 , —C(O)CF 3 , —C(O)CH 2 OH and —C(O)CH 2 -halogen.

6. The method of claim 5 wherein the compound has the formula

7. The method of claim 5 wherein the compound has the formula

8. The method of claim 5 wherein the compound has the formula

9. The method of claim 5 wherein the compound has the formula

10. The method of claim 4 wherein R 6 is —H or —CH 3 .

11. The method of claim 10 wherein one R 2 and R 3 is —H, or C1-4 optionally substituted alkyl and the other R 2 and R 3 is —OH, an ester or an ether, wherein the ester is optionally selected from the group consisting of —O—C(O)—CH 3 , —O—C(O)—CF 3 , —O—C(O)—CH 2 CH 3 and —O—C(O)—(CH 2 ) 2 CH 3 , and/or wherein one R 5 is —H or C1-4 optionally substituted alkyl and the other R 5 is —OH, —SH or an ester.

12. The method of claim 11 wherein R 4 in the β-configuration is —OH, an ester or an ether and R 4 in the α-configuration is or optionally substituted C 1-8 alkyl optionally selected from the group consisting of —CH 3 , —CF 3 , —CN, —C 2 H 5 , —C 2 F 5 , —CH═CH 2 , —CCH or both R 4 together are ═NOH.

13. The method of claim 4 wherein the formula 1 compound is 17α-ethynylandrost-5-ene-3β,7β,16α,17β-tetrol, 17α-ethynylandrost-5-ene-3α,7β,16α,17β-tetrol, 17α-ethynylandrost-5-ene-3β,7β,17β-triol, 17α-ethynylandrost-5-ene-3β,7β,17β-triol, 17β-ethynylandrost-5-ene-3β,7β,17α-triol, 17α-ethynylandrost-4-ene-3β,7β,17β-triol, 17α-ethynylandrostane-3β,7β,17β-triol, 17α-ethynylandrost-5-ene-3α,7β,17β-triol, 17α-ethynylandrost-4-ene-3α,7β,17β-triol, 17α-ethynylandrostane-3α,7β,17β-triol, 17α-ethynylandrost-5-ene-3β,7α,17β-triol, 17α-ethynylandrost-4-ene-3β,7α,17β-triol, 17α-ethynylandrostane-3β,7α,17β-triol, 17α-ethynylandrost-5-ene-3α,7α,17β-triol, 17α-ethynylandrost-4-ene-3α,7α,17β-triol, 17α-ethynylandrostane-3α,7α,17β-triol, 17α-ethynylandrost-5-ene-7β,17β-diol-3-one, 17α-ethynylandrost-5-ene-3β,17β-diol-7-one, 17α-ethynylandrost-5-ene-3α,17β-diol-7-one, 17α-chloroethynylandrost-5-ene-3β,7β,17β-triol, 17α-chloroethynylandrost-5-ene-3α,7β,17β-triol, 17α-ethynylandrost-5-ene-3β,4β,16α,17β-tetrol, 4-acetoxy-17α-ethynylandrost-4-ene-3β,16α,17β-triol, 17α-ethynylandrost-5-ene-3α,4β,16α,17β-tetrol, 4-acetoxy-17α-ethynylandrost-4-ene-3α,16α,17β-triol, 17α-ethynylandrost-5-ene-3β,11β,16α,17β-tetrol, 17α-ethynylandrost-5-ene-3α,11β,16α,17β-tetrol, 17α-ethynylandrost-5-ene-3β,11β,16β,17β-tetrol, 17β-ethynylandrost-5-ene-3β,11β,16β,17α-tetrol, 17α-ethynylandrost-5-ene-2β,3β,16α,17β-tetrol, 17α-ethynylandrost-5-ene-2β,3α,16α,17β-tetrol, 17α-ethynylandrost-5-ene-2α,3β,16α,17β-tetrol, 17α-ethynylandrost-5-ene-2α,3α,16α,17β-tetrol, or an analog of any of these compounds wherein the hydroxyl group at the 3-position, if present, is replaced with an ester, optionally selected from —OC(O)CH 3 and —OC(O)C 2 H 5 .

14. The method of claim 4 wherein the formula 1 compound is 17α-ethynylandrost-5-ene-3β,7β,17β-triol.

Assignments (9)