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EP-4736949-A2 - METHODS OF TREATING AND PREVENTING ENDOTHELIAL DYSFUNCTION USING BARDOXOLONE METHYL OR ANALOGS THEREOF

EP4736949A2EP 4736949 A2EP4736949 A2EP 4736949A2EP-4736949-A2

Abstract

The present invention concerns methods for treating and preventing endothelial dysfunction and related disorders, including, for example, pulmonary arterial hypertension, using bardoxolone methyl or analogs thereof.

Inventors

  • CHIN, MELANIE PEI-HENG
  • MEYER, COLIN J

Assignees

  • Reata Pharmaceuticals Holdings, LLC

Dates

Publication Date
20260506
Application Date
20140822

Claims (15)

  1. A compound of the formula: wherein: Y is: -(CH 2 ) m C(O)R c , wherein m is 0 and R c is: hydroxy; or heteroaryl (C≤8) , alkoxy (C≤8) , alkylamino (C≤8) , or a substituted version of any of these groups; -NHC(O)R e , wherein R e is: alkyl (C≤8) , a substituted alkyl (C≤8) ; or a pharmaceutically acceptable salt or tautomer thereof, for use in improving mitochondrial function in a patient in need thereof; wherein the patient has been identified as not having at least one of the following characteristics: (a) a history of left-sided myocardial disease; (b) an elevated B-type natriuretic peptide (BNP) level; (c) an elevated albumin/creatinine ratio (ACR); and (d) chronic kidney disease (CKD); wherein the term "substituted" means one or more hydrogen atom from the group so modified has been independently replaced by -OH, -F, -Cl, -Br, -I, -NH 2 , -NO 2 , -CO 2 H, -CO 2 CH 3 , -CN, -SH, -OCH 3 , -OCH 2 CH 3 , -C(O)CH 3 , -NHCH 3 , -NHCH 2 CH 3 , -N(CH 3 ) 2 , -C(O)NH 2 , -OC(O)CH 3 , or -S(O) 2 NH 2 .
  2. The compound for use of claim 1, wherein the patient has been identified as not having at least two of the characteristics.
  3. The compound for use of claim 1, wherein the patient has been identified as not having at least three of the characteristics, or not having all four of the characteristics.
  4. The compound for use of claim 1, wherein the patient does not have a history of left-sided myocardial disease.
  5. The compound for use of claim 1, wherein the patient does not have an elevated BNP level, optionally wherein the BNP level is not greater than 200 pg/mL.
  6. The compound for use of claim 1, wherein the patient does not have an elevated ACR, optionally wherein the ACR is not greater than 300 mg/g.
  7. The compound for use of claim 1, wherein the patient's estimated glomerular filtration rate (eGFR) is greater than or equal to 30 mL/min/1.73 m 2 , or greater than or equal to 45 mL/min/1.73 m 2 , or greater than or equal to 60 mL/min/1.73 m 2 .
  8. The compound for use of claim 1, wherein: (i) the patient has been identified as not having COPD; or (ii) the patient does not suffer from renal disease; or (iii) the patient does not have stage 4 CKD; or (iv) the patient has been identified as not having cancer; or (v) the patient has been identified as not having type 2 diabetes.
  9. The compound for use of claim 1, wherein the patient has chronic kidney disease (CKD) or exhibits one or more symptoms of CKD.
  10. The compound for use of claim 1, wherein the patient has been identified as having cardiovascular disease.
  11. The compound for use of claim 1, wherein the patient has been identified as having or at risk of having pulmonary hypertension, optionally wherein the pulmonary hypertension is pulmonary arterial hypertension.
  12. The compound for use of claim 1, wherein the patient is a human patient.
  13. The compound for use of claim 1, wherein the compound is formulated as hard or soft capsule or a tablet, optionally wherein the patient receives a daily dose of from 0.1 mg to 300 mg of the compound, or from about 0.5 mg to about 200 mg of the compound, or from about 2.5 mg to about 30 mg of the compound.
  14. The compound for use of claim 1, wherein the compound is formulated as a solid dispersion comprising (i) the compound and (ii) an excipient, optionally wherein the excipient is (a) a methacrylic acid - ethyl acrylate copolymer, or (b) a methacrylic acid - ethyl acrylate copolymer comprising methacrylic acid and ethyl acrylate at a 1:1 ratio.
  15. The compound for use of claim 1, wherein the compound is selected from:

Description

The present application claims the priority benefit of United States provisional application number 61/869,527, filed August 23, 2013, the entire contents of which are incorporated herein by reference. BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates generally to the fields of biology and medicine. More particularly, it concerns, in some aspects, methods for treating and/or preventing endothelial dysfunction in patients who are diagnosed with or at risk for cardiovascular disease (including patients diagnosed with or at risk for pulmonary arterial hypertension, other forms of pulmonary hypertension, atherosclerosis, restenosis, hyperlipidemia, hypercholesterolemia, metabolic syndrome, or obesity) and other diseases or conditions using bardoxolone methyl and analogs thereof. 2. Description of Related Art Diseases of the cardiovascular system frequently involve oxidative stress and inflammation in the affected tissues. Oxidative stress arises in cells when the production of antioxidant proteins, such as glutathione, catalase, and superoxide dismutase, is inadequate to cope with intracellular or local levels of reactive oxygen or nitrogen species, such as superoxide, hydrogen peroxide, and peroxynitrite. Although nitric oxide is an important signaling molecule, its excessive production can also contribute to oxidative stress. Inflammation is a biological process that provides resistance to infectious or parasitic organisms and the repair of damaged tissue. Inflammation is commonly characterized by localized vasodilation, redness, swelling, and pain, the recruitment of leukocytes to a site of infection or injury, production of inflammatory cytokines, such as TNF-α and IL-1, and production of reactive oxygen or nitrogen species. In the later stages of inflammation, tissue remodeling, angiogenesis, and scar formation (fibrosis) may occur as part of the wound healing process. Under normal circumstances, the inflammatory response is regulated and temporary, and resolves in an orchestrated fashion once the infection or injury has been dealt with adequately. However, acute inflammation can become excessive and life-threatening if regulatory mechanisms fail. Alternatively, inflammation can become chronic and cause cumulative tissue damage or systemic complications. Specialized cells activated by pro-inflammatory signaling pathways, such as macrophages, can be a significant source of reactive oxygen and nitrogen species, creating or perpetuating oxidative stress in surrounding tissues. Inflammatory cytokines, such as TNFα, IL-6, and gamma-interferon, can also stimulate the production of reactive oxygen/nitrogen species in a variety of cells and thereby promote oxidative stress. Endothelial dysfunction, the failure of vascular endothelial cells to perform their normal functions, is a common early feature of many cardiovascular diseases and related disorders, including atherosclerosis, hypertension, coronary artery disease, chronic kidney disease, pulmonary hypertension, vascular complications of diabetes, and cardiovascular complications of many chronic diseases. See, e.g., Pepine, 1998. Under normal circumstances, the endothelium (a single layer of cells lining essentially the entire vascular system) regulates the balance between vasoconstriction and vasodilation. It also exerts anticoagulant and antiplatelet properties and provides a physical barrier between the bloodstream and the rest of the body, regulating both cellular trafficking and the passage of fluid into tissue. Known risk factors for cardiovascular disease, including hyperlipidemia, cigarette smoking, and diabetes, are associated with endothelial dysfunction. Damage to the endothelium is believed to be a critical early step in the development of atherosclerotic plaques. Endothelial dysfunction can be detected clinically by elevations in the number of circulating endothelial cells (CECs). See, e.g., Burger (2012). A hallmark of endothelial dysfunction is impaired endothelium-dependent vasodilation, which is mediated by nitric oxide (NO) produced by endothelial nitric oxide synthase (eNOS), a constitutive form of NOS that is principally expressed in endothelial cells (e.g., Davignon, 2004). In healthy vasculature, NO produced by the endothelium diffuses to vascular smooth muscle cells (VSMC), where it activates guanylate cyclase and stimulates production of cyclic guanosine monophosphate (cGMP), thereby promoting relaxation of the VSMC and, consequently, vasodilation. Other functions of the endothelium (e.g., inhibition of platelet aggregation, inhibition of leukocyte adherence, and inhibition of VSMC proliferation) aare also mediated by NO. In dysfunctional endothelium, NO production is impaired. Oxidative stress is a major underlying factor in the development of endothelial dysfunction. Many risk factors associated with cardiovascular disease (e.g., hypertension, activation of the renin/angiotensin system, hypercholestero