Fumagillol-type compounds and methods of making and using same

Abstract

The present disclosure provides a fumagillol-type compound and its use in the treatment of medical conditions such as obesity. Pharmaceutical compositions and methods, eg, for treating obesity, are provided.

Description

[0001] Refer to related applications

[0002] This application claims priority to and benefit of US Provisional Patent Application No. 61 / 293,318, filed January 8, 2010, which is hereby incorporated by reference in its entirety. Background of the invention

[0003] Nearly 1.1 billion people worldwide are reported to be overweight. It is estimated that obesity affects more than 90 million people in the United States alone. Twenty-five percent of the U.S. population over the age of twenty is considered clinically obese. While being overweight or obese creates problems (e.g., restricted mobility, discomfort in confined spaces such as movie theaters or airplane seats, social difficulties, etc.), these conditions, especially clinical obesity, affect other aspects of health, namely, Diseases and other adverse health conditions associated with, exacerbated by, or caused by overweight or obesity. In the United States, an estimated 300,000 deaths are attributed to obesity-related co...

Examples

Embodiment 1

[0086] Compound A was tested in the MetAP2 enzyme assay. Table 1 indicates the inhibition results for various concentrations:

[0087] 1hr 200nM

[0088] In cellular assays, inhibition of MetAP2 was <10 nM.

Embodiment 2

[0090] Weight loss studies were performed in obese mice. The mice in this study were not genetically obese, but were induced to become obese by a high-fat diet before and during the study. Twelve-week-old C57BL / 6NTac mice maintained on a 60% fat diet before and during the study were divided into 7 groups of 8 mice each. The average mouse weight at the start of the study was approximately 47 g.

[0091] Mice were administered 1.0 mg / kg of Compound A in 10% macrogolglyceride laurate in deionized water. The mice received the drug once a day for 7 consecutive days. 11.9% weight loss in one week.

Embodiment 3

[0093] Three studies were performed using 18-20 week old C57BL / 6 mice. Study A was a 7-day screen consisting of feeding 18-20 week-old C57BL / 6 mice a 45% kcal fat diet for 14 weeks with 10% macrogolglyceride laurate in water or containing The same vehicle treatment with the same vehicle in the amount of Compound A at a daily dose of 1 mg / kg for 7 days. figure 1 The body weight loss effect of 1 mg / kg dose was shown.

[0094] Study B was a 10-day study that included 20-week-old C57BL / 6 mice receiving a 60% kcal fat diet for 14 weeks with either 10% DMSO or a drug containing 10% DMSO that provided a daily dose of 3 mg / kg Compound A for 10 consecutive days. The amount of drug treated with the same excipients. figure 2 The 7-day PO potency of Compound A at 3 mg / kg is depicted.

[0095] Study C was a 10-day study consisting of 20-week-old C57BL / 6 mice receiving a 60% kcal fat diet for 14 weeks with 10% DMSO or with 1 mg / kg or 3 mg / kg of compound 6-O per day. - (4-Dimethylamino...

[0001] Refer to related applications

[0002] This application claims priority to and benefit of US Provisional Patent Application No. 61 / 293,318, filed January 8, 2010, which is hereby incorporated by reference in its entirety. Background of the invention

[0003] Nearly 1.1 billion people worldwide are reported to be overweight. It is estimated that obesity affects more than 90 million people in the United States alone. Twenty-five percent of the U.S. population over the age of twenty is considered clinically obese. While being overweight or obese creates problems (e.g., restricted mobility, discomfort in confined spaces such as movie theaters or airplane seats, social difficulties, etc.), these conditions, especially clinical obesity, affect other aspects of health, namely, Diseases and other adverse health conditions associated with, exacerbated by, or caused by overweight or obesity. In the United States, an estimated 300,000 deaths are attributed to obesity-related co...

Examples

Embodiment 1

[0086] Compound A was tested in the MetAP2 enzyme assay. Table 1 indicates the inhibition results for various concentrations:

[0087] 1hr 200nM

[0088] In cellular assays, inhibition of MetAP2 was <10 nM.

Embodiment 2

[0090] Weight loss studies were performed in obese mice. The mice in this study were not genetically obese, but were induced to become obese by a high-fat diet before and during the study. Twelve-week-old C57BL / 6NTac mice maintained on a 60% fat diet before and during the study were divided into 7 groups of 8 mice each. The average mouse weight at the start of the study was approximately 47 g.

[0091] Mice were administered 1.0 mg / kg of Compound A in 10% macrogolglyceride laurate in deionized water. The mice received the drug once a day for 7 consecutive days. 11.9% weight loss in one week.

Embodiment 3

[0093] Three studies were performed using 18-20 week old C57BL / 6 mice. Study A was a 7-day screen consisting of feeding 18-20 week-old C57BL / 6 mice a 45% kcal fat diet for 14 weeks with 10% macrogolglyceride laurate in water or containing The same vehicle treatment with the same vehicle in the amount of Compound A at a daily dose of 1 mg / kg for 7 days. figure 1 The body weight loss effect of 1 mg / kg dose was shown.

[0094] Study B was a 10-day study that included 20-week-old C57BL / 6 mice receiving a 60% kcal fat diet for 14 weeks with either 10% DMSO or a drug containing 10% DMSO that provided a daily dose of 3 mg / kg Compound A for 10 consecutive days. The amount of drug treated with the same excipients. figure 2 The 7-day PO potency of Compound A at 3 mg / kg is depicted.

[0095] Study C was a 10-day study consisting of 20-week-old C57BL / 6 mice receiving a 60% kcal fat diet for 14 weeks with 10% DMSO or with 1 mg / kg or 3 mg / kg of compound 6-O per day. - (4-Dimethylamino...

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