(12) Patent Application Publication (10) Pub. No.: US 2017/0056379 A1 Chen Et Al
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US 2017.0056379A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0056379 A1 Chen et al. (43) Pub. Date: Mar. 2, 2017 (54) METHOD OF USING DOPAMINE ation of application No. 13/509,881, filed on Sep. 24, REUPTAKE INHIBITORS AND THEIR 2012, now Pat. No. 9,119,843, filed as application No. ANALOGS FOR TREATING DABETES PCT/US2010/058864 on Dec. 3, 2010. SYMPTOMIS AND DELAYING OR PREVENTING DABETES-ASSOCATED (60) Provisional application No. 61/266,740, filed on Dec. PATHOLOGIC CONDITIONS 4, 2009. (71) Applicant: CALIPER LIFE SCIENCES, INC., Hopkinton, MA (US) Publication Classification (72) Inventors: Hao Chen, Columbia, MD (US); Ming (51) Int. Cl. Liu, Rockville, MD (US); Malathi A6II 3/42.45 (2006.01) Sathyamoorthy, Ellicott City, MD A6II 45/06 (2006.01) (US); Qi Su, Columbia, MD (US); Lisa (52) U.S. Cl. Leary, Edgewater, MD (US); Wayne CPC ........... A61K 31/4245 (2013.01); A61K 45/06 Shaobin Zhong, Gaithersburg, MD (2013.01) (US) (21) Appl. No.: 15/350,221 (57) ABSTRACT (22) Filed: Nov. 14, 2016 Method of using dopamine reuptake inhibitors, e.g., Syd Related U.S. Application Data nonimine derivatives, for the management of diabetic symp (63) Continuation of application No. 14/841,664, filed on toms and associated complications or conditions, such as Aug. 31, 2015, now abandoned, which is a continu hyperglycemia and diabetic neuropathy. Patent Application Publication Mar. 2, 2017 Sheet 1 of 2 US 2017/0056379 A1 18O 160 i OO 1 OO 8O high fat D high fat N normal D normal N. With Control Mice Dunnett's O.05 Fig. 1 26O 240 1228O2 OOO | 16 O 140 12O high fat D high fat N normal D normal N. With Control Mice Dunnett's O.05 Fig. 2 Patent Application Publication Mar. 2, 2017 Sheet 2 of 2 US 2017/0056379 A1 6 O 40 4N Z Y 3O 2O t/ Y/ S high fat D high fat N normal D normal N Nantga Mice Fig. 3 high fat D high fat N normal D normal N With Control Mice Dunnett's O.05 Fig. 4 US 2017/0056379 A1 Mar. 2, 2017 METHOD OF USING DOPAMINE 0007 Diabetic conditions are often linked with altered REUPTAKE INHIBITORS AND THEIR central and sympathetic nervous systems. Most chronic ANALOGS FOR TREATING DABETES diabetic patients eventually develop neuropathy of different SYMPTOMIS AND DELAYING OR clinical manifestations. According to a statement made by PREVENTING DABETES-ASSOCATED the American Diabetes Association, the most common PATHOLOGIC CONDITIONS among the neuropathies are chronic sensorimotor distal symmetric polyneuropathy (DPN) and the autonomic neu CROSS-REFERENCE TO RELATED ropathies. Up to 50% of DPN may be asymptomatic but the APPLICATIONS patient is at risk of insensate injury to their feet and >80% of amputations follow a foot ulcer or injury. Additionally, 0001. The present application is a continuation of U.S. Such neuropathy also includes autonomic manifestations of patent application Ser. No. 14/841,664, filed Aug. 31, 2015, every system in the body, which causes substantial morbid which is a continuation of U.S. patent application Ser. No. ity and increased mortality, particularly when cardiovascular 13/509,881, filed Sep. 24, 2012, which is a U.S. National autonomic neuropathy (CAN) is present. Glucose and/or Stage of International Patent Application No. PCT/US2010/ insulin are not known to directly mediate sensory or noci 058864, filed Dec. 3, 2010, which claims the benefit of U.S. ceptive perceptions such as hypoalgesia or hyperalgesia Provisional Patent Application No. 61/266,740, filed Dec. 4, (different neuropathic manifestations), nor are they known 2009, the entire disclosures of which are incorporated by to be linked with cardiovascular autonomic regulations. reference herein. Literature reports indicate that strict glycemic control may mediate neuropathies, but not eliminate the symptoms FIELD OF INVENTION entirely. These indications point to other neurological 0002 The present invention relates to the field of phar mediators that 1) contribute to the regulation of glucose/ macological management of diabetes and various associated energy homeostasis and 2) are dis-regulated under pre disease manifestations. More specifically, the present inven diabetic or diabetic conditions (genetic and/or environmen tion provides a method of using dopamine reuptake inhibi tal factors). tors, including certain Sydnonimine derivatives, for the 0008 Epidemiological studies have linked child-hood management of diabetic symptoms and associated compli obesity and diabetes with neurological dysfunctions like cations or conditions, such as hyperglycemia and diabetic attention deficit hyperactive disorder (ADHD). These stud neuropathy. ies suggest that dopaminergic transmission that evolved to increase cognition is also coupled with attention and energy BACKGROUND OF THE INVENTION management (Campbell and Eisenberg, 2007). One of the working hypotheses regarding ADHD etiology is that 0003 Diabetes is a modern epidemic affecting an increas patients have handicapped energetic management between ingly large number of populations from industrial countries neuronal and glial cells (Russell, et al 2006). Besides to the developing world. The cost of managing diabetes in ADHD, there is a substantial body of clinical evidence and the United States alone is about S174 billion, S116 billion of research reports linking anxiety, stress and depression with which are directed towards medical care. diabetes. These mechanisms are still to be explored and 0004. The hallmark symptom of diabetes mellitus is understood. Nevertheless, the response of neuroendocrine, hyperglycemia, i.e. high levels of blood glucose (also known hypothalamic-pituitary-adrenal axis and sympathetic ner as blood Sugar). Such conditions are primarily the result of Vous system, to stressors may be key contributing factors to insufficient insulin production (Type I diabetes) or from the underlying etiology. Based on these studies, a panel of defects in response to insulin action (Type II diabetes). A experts has suggested that activation of the dopaminergic chronic diabetic condition causes serious complications or circuitry may be a viable and effective clinical management co-morbidities, such as heart disease, stroke, impaired renal paradigm (Blum et al., 2008). function, or nephropathy, high blood pressure, both central 0009 Diabetes alters the central and sympathetic nervous and peripheral nerve damage or neuropathy, cataracts and/or systems that may lead to behavior manifestations. Stress and blindness and amputations. depression, central nervous system conditions, may cause 0005 According to the National Diabetes Information metabolic changes leading to diabetes. These disease symp Clearinghouse (NDIC) report (a service provided by toms may share common roots. To further support the role National Institute of Diabetes and Digestive and Kidney of neuronendocrine system in diabetes, especially with Diseases, NIDDK, NIH), in the United States, in 2007 there regards to the role of dopaminergic function, there is a were 23.6 million (approximately 7.8 percent of the popu Substantial body of Supporting evidence from animal studies lation) diabetic patients along with 1.6 million new cases of When treated neonatally with monosodium glutamate, Wis diabetes diagnosed in the same year. About half (12.1 tar rats develop symptoms of Type II diabetes, i.e. hyper million) of the diabetic population is age 60 or older. glycemia, glucose intolerance, beta-cell morphological Moreover, an estimated 57 million American adults exhibit changes, and sensory and autonomic nerve changes includ pre-diabetic conditions (e.g. persistent hyperglycemic con ing the development of a hypoalgesic state. Concomitantly, ditions) in 2007, a warning sign of potential outbreak. there are noted changes in catecholamine synthesis in dif 0006. The etiology of diabetes is still under investigation. ferent peripheral tissues and sympathetic nerves (Morrison The primary focus of diabetic management is the reduction et al., 2007). of blood glucose levels. Few therapeutic initiatives with 0010. In one animal model of Type I diabetes (Sprague regard to diabetic management started with a neurological Dawley rats treated with Streptozotocin), a brief episode of approach. Mediating and attenuating diabetic neurological the chemically induced diabetes brought changes in dop symptoms are often afterthoughts. aminergic neurotransmission by reducing levels of dop US 2017/0056379 A1 Mar. 2, 2017 amine in a tissue specific manner. Notably, in the peripheral (glyburide). Metformin inhibits the release of glucose from (sympathetic) nervous system, dopamine content remains liver glycogen; Glibenclamide (and other Sulfonylureas), unperturbed at adrenal glands, blood serum and cardiac inhibits pancreatic beta-cell potassium channels, and thus ventricles; yet there is a 14 to 15 fold reduction of dopamine stimulates insulin secretion. Although these drugs are mostly in the stellate ganglion (physiologically, the human Stellate safe, they cannot be used in patients with compromised ganglion, or cervicothoracic ganglion, may be blocked for hepatic functions. There are other drugs that mediate the different medical conditions; reduction of catecholamine diabetic condition by alternative biochemical mechanisms, may be an indication of the reduction of catecholamine e.g. Stimulating insulin secretion (e.g. repaglinide), inhibit neurotransmission in the sympathetic nerves system leading ing glucose metabolism (e.g. glucosidase inhibitor, acar to conditions such as DPN). In the central nervous system, bose), mediating