IP Library › Granted Patent US 12,364,693
Granted Patent B2
US 12,364,693 · App. 17/739,757 · Granted Jul 22, 2025

Methods of treating metabolic diseases with fused bicyclic pyrazoles

Inventors: Yu-Hsin Tom Lin (Taipei, TW); Cheng-Chi Irene Wang (San Diego, CA)
Assignee: Belite Bio, Inc
A61K31/496A61K31/451A61K31/4523A61K31/4535A61K31/454A61K31/4545A61K31/497A61K31/501A61K31/5377A61K31/55A61P1/16A61P3/04A61P3/10
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Quick Facts
Patent No.
US 12,364,693
App. No.
17/739,757
Granted
Jul 22, 2025
Kind
B2
Abstract

Provided herein are heterocyclic derivative compounds and pharmaceutical compositions comprising said compounds that are useful for the treatment of retinal binding protein (RBP4) related diseases, such as obesity and the like.

Claims (20)

1. A method of treating a metabolic disease or disorder in a subject in need thereof, the method comprising administering to the subject a composition comprising a therapeutically effective amount of a compound having the structure:

or a pharmaceutically acceptable salt thereof, wherein the metabolic disease or disorder is obesity, type II diabetes, diabetic retinopathy, liver fibrosis, liver cancer, or liver cirrhosis.

2. The method of claim 1 , wherein the therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof is 25 mg per day, 50 mg per day, 75 mg per day, 100 mg per day, 150 mg per day, 200 mg per day, or 400 mg per day.

3. The method of claim 1 , wherein 24 hours after administration of the compound or a pharmaceutically acceptable salt thereof, the serum or plasma levels of RBP4 are reduced by at least 50% from baseline.

4. The method of claim 1 , wherein 24 hours after administration of the compound or a pharmaceutically acceptable salt thereof, the serum or plasma levels of RBP4 are reduced by at least 1 mg/dL.

5. The method of claim 1 , wherein the disease or disorder is non-proliferative diabetic retinopathy (NPDR) or proliferative diabetic retinopathy (PDR).

6. The method of claim 1 , wherein the compound is administered to the subject orally or intravenously.

7. The method of claim 3 , wherein 24 hours after administration of the compound or a pharmaceutically acceptable salt thereof, the serum or plasma levels of RBP4 are reduced by at least 65% from baseline.

8. The method of claim 6 , wherein when the compound is administered to the subject orally, the compound is administered at an oral dosage of about 1.0 mg to about-1000 mg.

9. The method of claim 1 , wherein the compound is administered to a subject or patient in an amount of up to 100 mg per day.

10. The method of claim 1 , wherein the compound is administered to a subject or patient in an amount of up to 50 mg per day.

11. The method of claim 1 , wherein the metabolic disease or disorder is obesity or type II diabetes.

12. The method of claim 1 , wherein the compound is administered once a day.

13. The method of claim 1 , wherein the subject is genetically, environmentally, dietarily, or socially predisposed to type II diabetes.

14. The method of claim 1 , wherein the metabolic disease or disorder is liver fibrosis, liver cancer, or liver cirrhosis.

15. The method of claim 1 , wherein administering the compound causes a clinical symptom of type II diabetes not to develop in a subject that is predisposed to type II diabetes but who does not yet experience or display symptoms of type II diabetes.

16. The method of claim 1 , wherein administering the compound reduces the development of obesity or its clinical symptoms.

17. The method of claim 1 , wherein the subject exhibits an abnormal accumulation of fat cells.

18. The method of claim 1 , wherein the subject is a mammal.

19. The method of claim 1 , wherein the composition is formulated as an oral dosage in the form of a tablet, a pill, a sachet, or a capsule of hard or soft gelatin.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 27, 2024
From: LIN, YU-HSIN TOM
To: BELITE BIO, INC.
Reel/Frame 068410/0159 →
Continuity (3)
Continuation 16622252
Provisional Application 62520359 · Jun 15, 2017
Related Publication 20220354844A1 · Nov 10, 2022
References Cited (111)
US 7632837B2 · Sun et al. · 2009 [cited by applicant]
US 8648038B2 · Defossa et al. · 2014 [cited by applicant]
US 8680137B2 · Sun et al. · 2014 [cited by applicant]
US 8980924B2 · Petrukhin et al. · 2015 [cited by applicant]
US 9333202B2 · Petrukhin et al. · 2016 [cited by applicant]
US 9434727B2 · Petrukhin · 2016 [cited by examiner]
US 9487509B2 · Kasai et al. · 2016 [cited by applicant]
US 9637450B2 · Petrukhin et al. · 2017 [cited by applicant]
US 9777010B2 · Petrukhin et al. · 2017 [cited by applicant]
US 9926271B2 · Petrukhin et al. · 2018 [cited by applicant]
US 9938291B2 · Petrukhin et al. · 2018 [cited by applicant]
US 9944644B2 · Petrukhin et al. · 2018 [cited by applicant]
US 10245259B2 · Lin et al. · 2019 [cited by applicant]
US 11007186B2 · Lin et al. · 2021 [cited by applicant]
US 11389444B2 · Lin · 2022 [cited by examiner]
US 12016853B2 · Lin et al. · 2024 [cited by applicant]
US 20100022530A1 · Schiemann et al. · 2010 [cited by applicant]
US 20110123521A1 · Monia · 2011 [cited by examiner]
US 20140066420A1 · Kasai et al. · 2014 [cited by applicant]
US 20150315197A1 · Petrukhin et al. · 2015 [cited by applicant]
US 20160004668A1 · Rowles et al. · 2016 [cited by applicant]
US 20160046648A1 · Petrukhin et al. · 2016 [cited by applicant]
US 20160046649A1 · Petrukhin et al. · 2016 [cited by applicant]
US 20170114072A1 · Yang et al. · 2017 [cited by applicant]
US 20210228563A1 · Lin et al. · 2021 [cited by applicant]
US 20220387400A1 · Lin et al. · 2022 [cited by applicant]
US 20230312585A1 · Petrukhin et al. · 2023 [cited by applicant]
AU 2015336480A1 · 2017 [cited by applicant]
AU 2015336480A2 · 2017 [cited by applicant]
CN 101294956A · 2008 [cited by applicant]
EP 2202223A1 · 2010 [cited by applicant]
EP 3210973A1 · 2017 [cited by applicant]
WO WO0174164A1 · 2001 [cited by applicant]
WO WO2009143390A2 · 2009 [cited by applicant]
WO WO2012071369A2 · 2012 [cited by applicant]
WO WO2013166037A1 · 2013 [cited by applicant]
WO WO2014151936A1 · 2014 [cited by applicant]
WO WO2014151959A1 · 2014 [cited by applicant]
WO WO2014152013A1 · 2014 [cited by applicant]
WO WO2014152018A1 · 2014 [cited by applicant]
WO WO2014160409A1 · 2014 [cited by applicant]
WO WO2015168286A1 · 2015 [cited by applicant]
WO WO2016063933A1 · 2016 [cited by applicant]
WO WO2018232150A1 · 2018 [cited by applicant]
WO WO2020028723A1 · 2020 [cited by applicant]
Bartlett “Exploiting Chemical Diversity for Drug Discovery” Edited by Paul A Bartlett and Michael Entzeroth, The Royal Society of Chemistry, 2006, pp. 113-118. [cited by examiner]
“Find ETDs Home » Thesis Resources » Find ETDs” Online: “https://ndltd.org/thesis-resources/find-etds/” Accessed Jan. 31, 2023. [cited by examiner]
Irwin “Zinc—A Free Database of Commercially Available Compounds for Virtual Screening” J. Chem. Inf. Model. 2005, 45, 177-182. [cited by examiner]
Kim “PubChem in 2021: new data content and improved web interfaces” Nucleic Acids Research, 2021, vol. 49, Database issue Published online Nov. 5, 2020. [cited by examiner]
STN Registry/Zregistry (CAS Registrysm) Sep. 2016 2 pages. [cited by examiner]
Graham, N Engl J Med 2006;354:2552-63. [cited by examiner]
Gong, Research progress on role of serum retinol-binding protein 4 in development of metabolic related diseases, Shandong Yiyao (2015), 55(19), 98-100. [cited by examiner]
Bhat, Serum retinol-binding protein, obesity, and insulin resistance, Vitamin-Binding Proteins (2014), 31-47. [cited by examiner]
Aguilera CM et al.: Alterations in plasma and tissue lipids associated with obesity and metabolic syndrome. Clin Sci (Lond). Feb. 2008;114(3):183-193. [cited by applicant]
Anon: Diagnosis and Classification of Diabetes Mellitus. 2012 Diabetes care, 35 Suppl 1, pp. S64-S71. [cited by applicant]
Attie AD et al.: Adipocyte metabolism and obesity. J Lipid Res. Apr. 2009;50 Suppl:S395-S399. [cited by applicant]
Cannon: Burger's Medicinal Chemistry and Drug Discovery 1995, Fifth Edition, I: Principles and Practice, Chap. 19, John Wiley & Sons, Inc., 783-802 (1995). [cited by applicant]
Chalasani et al.: The diagnosis and management of non-alcoholic fatty liver disease: Practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American… [cited by applicant]
Choe et al.: Adipose Tissue Remodeling Its Role in Energy Metabolism and Metabolic Disorders. Front Endocrinol (Lausanne). Apr. 13, 2016;7:30. [cited by applicant]
Cooke et al.: Type 1 diabetes mellitus in pediatrics. Pediatr Rev. Nov. 2008;29(11):374-384; quiz 385. [cited by applicant]
European Patent Application No. 18817386.8 Extended European Search Report dated Feb. 5, 2021. [cited by applicant]
Fabbrini et al.: Alterations in adipose tissue and hepatic lipid kinetics in obese men and women with nonalcoholic fatty liver disease. Gastroenterology 2008;134:424-431. [cited by applicant]
Goto et al.: Farnesol, an isoprenoid, improves metabolic abnormalities in mice via both PPAR-dependent and -independent pathways. Am J Physiol Endocrinol Metab. Nov. 2011;301(5):E1022-1032. [cited by applicant]
Graham et al.: Retinol-Binding Protein 4 and Insulin Resistance in Lean, Obese, and Diabetic Subjects. N. Engl J Med. 354:2552-2563 (2006). [cited by applicant]
Johansson et al.: Effect of fenretinide and low-dose tamoxifen on insulin sensitivity in premenopausal women at high risk for breast cancer. Cancer Res. Nov. 15, 2008;68(22):9512-9518. [cited by applicant]
Jung et al.: Obesity and Its Metabolic Complications: The Role of Adipokines and the Relationship between Obesity, Inflammation, Insulin Resistance, Dyslipidemia and Nonalcoholic Fatty Liver Disease. Int J Mol Sci. Apr.… [cited by applicant]
Kahn et al.: Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature. Dec. 14, 2006;444(7121):840-846. [cited by applicant]
Koh et al.: Fenretinide ameliorates insulin resistance and fatty liver in obese mice. Biol Pharm Bull. 2012;35(3):369-375. [cited by applicant]
Li et al.: Serum retinol-binding protein 4 levels in patients with diabetic retinopathy. The Journal of International Medical Research, 38:95-99, 2010. [cited by applicant]
Moon et al.: N-(4-Hydroxyphenyl)retinamide, a new retinoid for prevention of breast cancer in the rat. Cancer Res. Apr. 1979;39(4):1339-1346. [cited by applicant]
Moraes-Vieira et al.: RBP4 Activates Antigen-Presenting Cells, Leading to Adipose Tissue Inflammation and Systemic Insulin Resistance. Cell Metab. Mar. 4, 2014;19(3):512-526. [cited by applicant]
Okada-Iwabu et al.: Perspective of Small-Molecule AdipoR Agonist for Type 2 Diabetes and Short Life in Obesity. Diabetes Metab J. Oct. 2015;39(5):363-372. [cited by applicant]
PCT/US2019/044754 International Search Report and Written Opinion dated Nov. 27, 2019. [cited by applicant]
PCT/US2018/037593 International Preliminary Report on Patentability dated Dec. 17, 2019. [cited by applicant]
PCT/US2018/037593 International Search Report and Written Opinion dated Aug. 30, 2018. [cited by applicant]
PCT/US2018/037597 International Search Report and Written Opinion dated Aug. 28, 2018. [cited by applicant]
PCT/US2018/037606 International Preliminary Report on Patentability dated Dec. 17, 2019. [cited by applicant]
PCT/US2018/037606 International Search Report and Written Opinion dated Aug. 28, 2018. [cited by applicant]
Postic: Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice. J. J Clin Invest 2008;118:829-838. [cited by applicant]
Preitner et al.: Long-term Fenretinide treatment prevents high-fat diet-induced obesity, insulin resistance, and hepatic steatosis. Am J Physiol Endocrinol Metab. Dec. 2009;297(6):E1420-E1429. [cited by applicant]
Savage et al.: Disordered Lipid Metabolism and the Pathogenesis of Insulin Resistance. Physiol Rev. Apr. 2007;87(2):507-520. [cited by applicant]
Taiwan Patent Application No. 107120497 Office Action/Search Report. [cited by applicant]
Taiwan Patent Application No. 107120499 Office Action. [cited by applicant]
Taiwan Patent Application No. 107120499 Office Action/Search Report. [cited by applicant]
Tilg et al.: Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology. Nov. 2010;52(5):1836-1846. [cited by applicant]
U.S. Appl. No. 16/008,838 Restriction Requirement dated Sep. 21, 2018. [cited by applicant]
U.S. Appl. No. 16/272,911 Restriction Requirement dated Mar. 23, 2020. [cited by applicant]
U.S. Appl. No. 16/622,252 Final Office Action dated Oct. 20, 2021. [cited by applicant]
U.S. Appl. No. 16/622,252 Office Action dated Jun. 29, 2021. [cited by applicant]
U.S. Appl. No. 17/228,590 Office Action dated Jun. 7, 2023. [cited by applicant]
U.S. Appl. No. 17/228,590 Restriction Requirement dated Apr. 7, 2023. [cited by applicant]
Venkatesh et al.: Role of the Development Scientist in Compound Lead Selection and Optimization. J. Pharm. Sci. 89(2):145-154 (Feb. 2000). [cited by applicant]
Wang: Correlation of retinol binding protein 4 with metabolic indexes of glucose and lipid, bile cholesterol saturation index. 40(6):657-665 (2015) DOI:10.11817/j.issn.1672-7347.2015.06.014. [cited by applicant]
West: Solid Solutions. Solid State Chemistry and Its Applications. John Wiley & Sons. Chapter 10:358 (1984). [cited by applicant]
Wolff: Burger's Medicinal Chemistry and Drug Discovery. 5th Ed. Part 1, pp. 975-977 (1995). [cited by applicant]
Yang et al.: Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Nature 436(7049):356-362 (2005). [cited by applicant]
Bluher et al.: Does Retinol-Binding Protein 4 Cause or Reflect Fatty Liver Disease. Hepatology. 48(1):4-6 (2008). [cited by applicant]
European Patent Application No. EP18816926.2 Examination Report dated Mar. 4, 2024. [cited by applicant]
European Patent Application No. EP19845117.1-1112 Communication Pursuant to Article 94(3) EPC issued Jun. 21, 2022. [cited by applicant]
European Patent Application No. EP19845117.1-1112 Communication Pursuant to Article 94(3) EPC issued Oct. 23, 2023. [cited by applicant]
Tan et al.: Suppression of retinol-binding protein 4 with RNA oligonucleotide prevents high-fat diet-induced metabolic syndrome and non-alcoholic fatty liver disease in mice. Department of Medical & Molecular BioScience… [cited by applicant]
Yang et al.: Berberine ameliorates non-alcoholic steatohepatitis in ApoE-/- mice. Center for Translational Medicine. 14:4134-4140 (2017). [cited by applicant]
Zhang et al.: Anti-diabetic effects of cinnamaldehyde and berberine and their impacts on retinol-binding protein 4 expression in rats with type 2 diabetes mellitus. Chinese Medical Association. 121(21):2124-8 (2022). [cited by applicant]
Balagopal, Prabhakaran et al. Reduction of elevated serum retinol binding protein in obese children by lifestyle intervention: association with subclinical inflammation. The Journal of clinical endocrinology and metabol… [cited by applicant]
EP18817386.8 European Examination Report dated Mar. 27, 2024. [cited by applicant]
Esteve, Eduardo et al. Adipocytokines and insulin resistance: the possible role of lipocalin-2, retinol binding protein-4, and adiponectin. Diabetes care 32(Suppl 2):S362-S367 (2009). [cited by applicant]
Gavi, Shai et al. Retinol-binding protein 4 is associated with insulin resistance and body fat distribution in nonobese subjects without type 2 diabetes. The Journal of clinical endocrinology and metabolism 92(5):1886-1… [cited by applicant]
Klöting, Nora et al. Serum retinol-binding protein is more highly expressed in visceral than in subcutaneous adipose tissue and is a marker of intra-abdominal fat mass. Cell metabolism 6(1):79-87 (2007). [cited by applicant]
Nair, Anup Kumar et al. Case-control analysis of SNPs in GLUT4, RBP4 and STRA6: association of SNPs in STRA6 with type 2 diabetes in a South Indian population. PLOS One 5(7):e11444, 1-8 (2010). [cited by applicant]
Ost, Anita et al. Retinol-binding protein-4 attenuates insulin-induced phosphorylation of IRS1 and ERK1/2 in primary human adipocytes. FASEB journal 21(13):3696-3704 (2007). [cited by applicant]
Samaras, Katherine et al. Subcutaneous and visceral adipose tissue gene expression of serum adipokines that predict type 2 diabetes. Obesity 18(5):884-889 (2010). [cited by applicant]
Cited By (1)
US 12,714,700