Compositions and methods for inhibiting arginase activity
AssigneeThe Trustees of the University of Pennsylvania
InventorsDavid Christianson, Ricky Baggio, Daniel Elbaum
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Abstract
Compositions and methods for inhibiting arginase activity, including arginase activity in a mammal, are provided. Methods of making the compositions of the invention are also provided as are methods of using the compositions therapeutically. The compositions described herein are useful for alleviating or inhibiting a variety of arinase- and NO synthase-related disorders, including heart diseae, gastrointestinal motility disorders, and penile erectile dysfunction in humans.
Claims26
A method of inhibiting the activity of an arginase, the method comprising contacting the arginase with a compound having the structure
- HOOC—CH(NH2)—X1—X2—X3—X4—B(OH)2
- wherein each of X1, X2, X3, and X4 is selected from the group consisting of —(CH2)—, —S—, —O—, —(NM)—, and —(N-alkyl)—.
A method of inhibiting the activity of an arginase in a mammal, the method comprising administering to the mammal a composition comprising a pharmaceutically acceptable carrier and an arginase inhibitor having the structure
- HOOC—CH(NH2)—X1—X2—X3—X4—B(OH)2
- wherein each of X1, X2, X3, and X4 is selected from the group consisting of —(CH2)—, —S—, —O—, —(NH)—, and —(N-alkyl)—.
A method of treating a disorder associated with an abnormally low level of nitric oxide synthase activity in a tissue of a human, the method comprising administering to the human a composition comprising a pharmaceutically acceptable carrier and an arginase inhibitor having the structure
- HOOC—CH(NH2)—X1—X2—X3—X4—B(OH)2
- wherein each of X1, X2, X3, and X4 is selected from the group consisting of —(CH2)—, —S—, —O—, —(NH)—, and —(N-alkyl)—.
A method of relaxing smooth muscle in a mammal, the method comprising administering to the mammal a composition comprising a pharmaceutically acceptable carrier and an arginase inhibitor having the structure
- HOOC—CH(NH2)—X1—X2—X3—X4—B(OH)2
- wherein each of X1, X2, X3, and X4 is selected from the group consisting of —(CH2)—, —S—, —O—, —(NH)—, and —(N-alkyl)—.
A method of making a compound having the structure
- HOOC—CH(NH2)—CH2—CH2—CH2—CH2—B,(OH)2,
- the method comprising contacting a molecule of the tert-butyl ester of 2(S)-N-(tert-butyloxycarbonyl)-6-[(1S,2S,3R,5S)-(+)-pinanedioxaboranyl]-hexanoic acid in an organic solvent with BCl3.
A method of making a compound having the structure
- HOOC—CH(NH2)—CH2—CH2—CH2—CH2—B(OH)2,
- the method comprising the steps of
- (a) mixing a solution of the tert-butyl ester of 2(S)-N-(tert-butyloxycarbonyl)-glutamic acid in tetrahydrofuran with triethylamine and ethyl chloroformate to produce a first mixture, removing the resulting triethylammonium hydrochloride salt by filtration, and treating the remaining mixture with an aqueous solution of sodium borohydride to provide a first compound, wherein the first compound is the tert-butyl ester of 2(S)-N-(tert-butyloxycarbonyl)-5-hydroxypentanoic acid;
- (b) subjecting the first compound to Swem oxidation to produce a second compound;
- (c) subjecting the second compound to a Wittig reaction in the presence of triphenylphosphonium methylide to produce a third compound;
- (d) mixing a solution of BH3 with the third compound in the presence of tetrahydrofuran to produce a second mixture;
- (e) adding (1S ,2S,3R,5S)-(+)-pinanediol to the second mixture to produce a fourth compound, wherein the fourth compound is the tert-butyl ester of 2(S)-N-(tert-butyloxycarbonyl)-6-[(1S,2S,3R,5S)-(+)-pinanedioxaboranyl]-hexanoic acid;
- and
- (f) mixing the fourth compound with BCl3 in the presence of CH2Cl2 to produce a compound having the structure
- HOOC—CH(NH2)—CH2—CH2—CH2—CH2—B(OH)2.
A method of alleviating erectile dysfunction in a human, the method comprising administering to the human a pharmaceutical composition comprising an arginase inhibitor having the structure
- HOOC—CH(NH2)—X1—X2—X3—X4—B(OH)2
- wherein each of X1, X2, X3, and X4 is selected from the group consisting of —(CH2)—, —S—, —O—, —(NH)—, and —(N-alkyl)—.
A method of treating a disorder associated with an abnormally high level of arginase activity in a tissue of a human, the method comprising administering to the human a composition comprising a pharmaceutically acceptable carrier and an arginase inhibitor having the structure
- HOOC—CH(NH2)—X1—X2—X3—X4—B(OH)2
- wherein each of X1, X2, X3, and X4 is selected from the group consisting of —(CH2)—, —S—,—O—, —(NH)—, and —(N-alkyl)—.
Dependencies are inferred from the claim text.