Using adiponectin receptor agonists to treat inflammation and bone diseases in diabetes

11655,212

17/550834

December 14, 2021

Disclosed herein are adiponectin receptor agonists and methods of using the same for the treatment of inflammation or bone loss in a subject.

Trustees of Tufts College (Medford, MA, US)

Trustees of Tufts College (Medford, MA, US)

1. A compound of formula [chemical expression included] or a pharmaceutically acceptable salt thereof, wherein R 1 is —C(═O)R 4 ; R 4 is a halo-substituted phenyl, an unsubstituted phenyl, or a C 1 -C 4 alkyl; R 2 is a C 1 -C 4 alkoxyl, hydrogen, or a halo; and R 3 is hydrogen or a C 1 -C 4 alkyl; or wherein R 1 is an unsubstituted phenyl; R 2 is a C 1 -C 4 alkoxyl or hydrogen; and R 3 is hydrogen or a C 1 -C 4 alkyl; and wherein if R 1 is —C(═O)R 4 and R 4 is a 4-chloro substituted phenyl, R 2 and R 3 are not both hydrogen; if R 1 is —C(═O)R 4 and R 4 is the unsubstituted phenyl, (i) R 2 and R 3 are not both hydrogen or (ii) R 2 and R 3 are not respectively 4-chloro and hydrogen; if R 1 is —C(═O)R 4 and R 4 is methyl, R 2 and R 3 are not respectively 3,4-dichloro and hydrogen, 3,4-dichloro and hydrogen, or 4-bromo and hydrogen; if R 1 is —C(═O)R 4 and R 4 is ethyl, R 2 and R 3 are not respectively 3,4-dichloro and hydrogen; and if R 1 is phenyl, R 2 and R 3 are not respectively hydrogen and methyl.

2. The compound of claim 1 , wherein the compound is [chemical expression included] [chemical expression included] or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein the compound is [chemical expression included]

4. The compound of claim 1 , wherein the compound is [chemical expression included]

5. A pharmaceutical composition comprising the compound according to claim 1 and a pharmaceutically acceptable excipient, carrier, or diluent.

6. A method for the treatment of inflammation a subject, the method comprising administering an effective amount of the compound according to claim 1 .

7. The method of claim 6 , wherein the subject has chronic inflammation.

8. The method of claim 6 , wherein the subject has diabetes.

9. The method of claim 6 , wherein the subject is obese.

10. The method of claim 6 , wherein the subject has an infection.

11. The method of claim 10 , wherein the subject suffers from sepsis, septic shock, or endotoxemia.

12. The method of claim 6 , wherein administering the effective amount of the compound decreases fasting blood glucose in the subject.

13. The method of claim 6 , wherein administering the effective amount of the compound inhibits or reduces expression of a proinflammatory cytokine in the subject.

14. The method of claim 6 , wherein administering the effective amount of the compound increases expression of an anti-inflammatory cytokine in the subject.

15. The method of claim 6 , wherein the compound is [chemical expression included]

16. A method for the treatment of bone loss a subject, the method comprising administering an effective amount of the compound according to claim 1 .

17. The method of claim 16 , wherein the subject has periodontitis.

18. The method of claim 16 , wherein the subject has type 2 diabetes (T2D)-associated periodontitis.

19. The method of claim 16 , wherein administering the effective amount of the compound increases autophagy in osteoclasts.

20. The method of claim 16 , wherein the compound is [chemical expression included]

20050250792 November 2005 Thom

Curtis, Michael J.et al. “Experimental design and analysis and their reporting II: Updated and simplified guidance for authors and peer reviewers.” British journal of pharmacology 175, No. 7 (2018): 987-993. cited by applicant
Daassi, Dhouha et al. “Differential expression patterns of MafB and c-Maf in macrophages in vivo and in vitro.” Biochemical and biophysical research communications 473, No. 1 (2016): 118-124. cited by applicant
Deepa, Sathyaseelan S. et al. “APPL1: role in adiponectin signaling and beyond.” American Journal of Physiology-Endocrinology and Metabolism 296, No. 1 (2009): E22-E36. cited by applicant
Diggins, Nicole L. et al. “APPL1 is a multifunctional endosomal signaling adaptor protein.” Biochemical Society Transactions 45, No. 3 (2017): 771-779. cited by applicant
Du, Meng et al. “The LPS-inducible IncRNA Mirt2 is a negative regulator of inflammation.” Nature communications 8, No. 1 (2017): 1-18. cited by applicant
Folco, Eduardo J. et al. “Adiponectin inhibits pro-inflammatory signaling in human macrophages independent of interleukin-10.” Journal of Biological chemistry 284, No. 38 (2009): 25569-25575. cited by applicant
Foster, Simmie L. et al. “Gene-specific control of the TLR-induced inflammatory response.” Clinical immunology 130, No. 1 (2009): 7-15. cited by applicant
Hirotani, Tomonori et al. “Regulation of lipopolysaccharide-inducible genes by MyD88 and Toll/IL-1 domain containing adaptor inducing IFN-β.” Biochemical and biophysical research communications 328, No. 2 (2005): 383-392. cited by applicant
Kilkenny, Carol et al. “Animal research: reporting in vivo experiments: the ARRIVE guidelines.” British journal of pharmacology 160, No. 7 (2010): 1577. cited by applicant
Kawai, Taro et al. “The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors.” Mature immunology 11, No. 5 (2010): 373-384. cited by applicant
Kim, James L. et al. “The transcription factor c-Maf controls the production of interleukin-4 but not other Th2 cytokines.” Immunity 10, No. 6 (1999): 745-751. cited by applicant
Kim, Mi Jin et al. “Globular adiponectin inhibits lipopolysaccharide-primed inflammasomes activation in macrophages via autophagy induction: the critical role of AMPK signaling.” International journal of molecular sciences 18, No. 6 (2017): 1275. cited by applicant
Kishimoto, Kazuya et al. “TAK1 mitogen-activated protein kinase kinase kinase is activated by autophosphorylation within its activation loop.” Journal of Biological Chemistry 275, No. 10 (2000): 7359-7364. cited by applicant
Kobashi, Chikaaki et al. “Adiponectin inhibits endothelial synthesis of interleukin-8.” Circulation research 97, No. 12 (2005): 1245-1252. cited by applicant
Kumada, Masahiro et al. “Adiponectin specifically increased tissue inhibitor of metalloproteinase-1 through interleukin-10 expression in human macrophages.” Circulation 109, No. 17 (2004): 2046-2049. cited by applicant
Lamothe, Betty et al. “Site-specific Lys-63-linked tumor necrosis factor receptor-associated factor 6 auto-ubiquitination is a critical determinant of IκB kinase activation.” Journal of Biological Chemistry 282, No. 6 (2007): 4102-4112. cited by applicant
Lian, Junxiang et al. “Potential roles of miR-335-5p on pathogenesis of experimental periodontitis.” Journal of periodontal research 55, No. 2 (2020): 191-198. cited by applicant
Lovren, Fina et al. “Adiponectin primes human monocytes into alternative anti-inflammatory M2 macrophages.” American Journal of Physiology-Heart and Circulatory Physiology 299, No. 3 (2010): H656-H663. cited by applicant
Mandal, Palash et al. “The anti-inflammatory effects of adiponectin are mediated via a heme oxygenase-1-dependent pathway in rat Kupffer cells.” Hepatology 51, No. 4 (2010): 1420-1429. cited by applicant
Mandal, Palash et al. “Molecular mechanism for adiponectin-dependent M2 macrophage polarization: link between the metabolic and innate immune activity of full-length adiponectin.” Journal of Biological Chemistry 286, No. 15 (2011): 13460-13469. cited by applicant
Mao, Liufeng et al. “Absence of Appl2 sensitizes endotoxin shock through activation of PI3K/Akt pathway.” Cell & Bioscience 4, No. 1 (2014): 1-10. cited by applicant
Mao, Xuming et al. “APPL1 binds to adiponectin receptors and mediates adiponectin signalling and function.” Nature cell biology 8, No. 5 (2006): 516-523. cited by applicant
Masamoto, Yosuke et al. “Adiponectin enhances antibacterial activity of hematopoietic cells by suppressing bone marrow inflammation.” Immunity 44, No. 6 (2016): 1422-1433. cited by applicant
McGrath, John C. et al. “Implementing guidelines on reporting research using animals (ARRIVE etc.): new requirements for publication in BJP.” British journal of pharmacology 172, No. 13 (2015): 3189-3193. cited by applicant
Medzhitov, Ruslan et al. “Transcriptional control of the inflammatory response.” Nature Reviews Immunology 9, No. 10 (2009): 692-703. cited by applicant
Murray, Peter J. et al. “Macrophage activation and polarization: nomenclature and experimental guidelines.” Immunity 41, No. 1 (2014): 14-20. cited by applicant
Murray, Peter J. et al. “Restraint of inflammatory signaling by interdependent strata of negative regulatory pathways.” Nature immunology 13, No. 10 (2012): 916-924. cited by applicant
Nicolas S. et al. “Adiponectin: an endogenous molecule with anti-inflammatory and antidepressant properties?”. Med Sci (Paris). May 2018;34(5):417-423. French, doi: 10.1051/medsci/20183405014. Epub Jun. 13, 2018. PMID: 29900844. cited by applicant
Harding, Simon D. et al. “The IUPHAR/BPS Guide to Pharmacology in 2018: updates and expansion to encompass the new guide to Immunopharmacology.” Nucleic acids research 46, No. D1 (2018): D1091-D1106. cited by applicant
Ohashi, Koji et al. “Adiponectin promotes macrophage polarization toward an anti-inflammatory phenotype.” Journal of Biological Chemistry 285, No. 9 (2010): 6153-6160. cited by applicant
Okada-Iwabu, Miki et al. “A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity.” Nature 503, No. 7477 (2013): 493-499. cited by applicant
Ouchi, Noriyuki et al. “Adiponectin as an anti-inflammatory factor.” Clinica chimica acta 380, No. 1-2 (2007): 24-30. cited by applicant
Piao, Wenji et al. “Endotoxin tolerance dysregulates MyD88-and Toll/IL-1R domain-containing adapter inducing IFN-β-dependent pathways and increases expression of negative regulators of TLR signaling.” Journal of leukocyte biology 86, No. 4 (2009): 863-875. cited by applicant
Tilija Pun et al. “Globular adiponectin causes tolerance to LPS-induced TNF-α expression via autophagy induction in RAW 264.7 macrophages: involvement of SIRT1/FoxO3A axis” PloS one 10, No. 5 (2015): e0124636. cited by applicant
Salomao, Reinaldo et al. “Bacterial sensing, cell signaling, and modulation of the immune response during sepsis.” Shock 38, No. 3 (2012): 227-242. cited by applicant
Sattar, Naveed et al. “Adiponectin and coronary heart disease: a prospective study and meta-analysis.” Circulation 114, No. 7 (2006): 623-629. cited by applicant
Skaug, Brian et al. “The role of ubiquitin in NF-κB regulatory pathways.” Annual review of biochemistry 78 (2009): 769-796. cited by applicant
Thakur, Varsha et al. “Adiponectin normalizes LPS-stimulated TNF-α production by rat Kupffer cells after chronic ethanol feeding.” American Journal of Physiology—Gastrointestinal and Liver Physiology 290, No. 5 (2006): G998-G1007. cited by applicant
Tilija Pun et al. “Adiponectin inhibits inflammatory cytokines production by Beclin-1 phosphorylation and B-cell lymphoma 2 mRNA destabilization: role for autophagy induction.” British Journal of Pharmacology 175, No. 7 (2018): 1066-1084. cited by applicant
Tu, Qisheng et al. “Adiponectin inhibits osteoclastogenesis and bone resorption via APPL1-mediated suppression of Akt1.” Journal of Biological Chemistry 286, No. 14 (2011): 12542-12553. cited by applicant
Van Den Bosch, Mirjam WM et al. “LPS induces the degradation of programmed cell death protein 4 (PDCD4) to release Twist2, activating c-Maf transcription to promote interleukin-10 production.” Journal of Biological Chemistry 289, No. 33 (2014): 22980-22990. cited by applicant
Wang, Nan et al. “Molecular mechanisms that influence the macrophage M1-M2 polarization balance.” Frontiers in immunology 5 (2014): 614. cited by applicant
Wess, Jurgen “G-protein-coupled receptors: molecular mechanisms involved in receptor activation and selectivity of G-protein recognition.” The FASEB Journal 11, No. 5 (1997): 346-354. cited by applicant
Wolf, Anna M. et al. “Adiponectin induces the anti-inflammatory cytokines IL-10 and IL-1RA in human leukocytes.” Biochemical and biophysical research communications 323, No. 2 (2004): 630-635. cited by applicant
Wu, X. et al. “An adiponectin receptor agonist reduces type 2 diabetic periodontitis.” Journal of dental research 98, No. 3 (2019): 313-321. cited by applicant
Wulster-Radcliffe, Meghan C. et al. “Adiponectin differentially regulates cytokines in porcine macrophages.” Biochemical and biophysical research communications 316, No. 3 (2004): 924-929. cited by applicant
Xie, Qing et al. “Regulation of c-Maf and αA-crystallin in ocular lens by fibroblast growth factor signaling.” Journal of Biological Chemistry 291, No. 8 (2016): 3947-3958. cited by applicant
Xu, Mo et al. “c-MAF-dependent regulatory T cells mediate immunological tolerance to a gut pathobiont.” Nature 554, No. 7692 (2018): 373-377. cited by applicant
Xuan, Dongying et al. “Epigenetic modulation in periodontitis: interaction of adiponectin and JMJD3-IRF4 axis in macrophages.” Journal of cellular physiology 231, No. 5 (2016): 1090-1096. cited by applicant
Yamaguchi, Noboru et al. “Adiponectin inhibits Toll-like receptor family-induced signaling.” FEBS letters 579, No. 30 (2005): 6821-6826. cited by applicant
Yamauchi, Toshimasa et al. “Cloning of adiponectin receptors that mediate antidiabetic metabolic effects.” Nature 423, No. 6941 (2003): 762-769. cited by applicant
Yokota, Takafumi et al. “Adiponectin, a new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages.” Blood, The Journal of the American Society of Hematology 96, No. 5 (2000): 1723-1732. cited by applicant
Zhang, Jin et al. “Exercise-induced irisin in bone and systemic irisin administration reveal new regulatory mechanisms of bone metabolism.” Bone research 5, No. 1 (2017): 1-14. cited by applicant
Zhang, Lan et al. “Adiponectin ameliorates experimental periodontitis in diet-induced obesity mice.” PloS one 9, No. 5 (2014): e97824. cited by applicant
U.S. Appl. No. 63/125,362, filed Dec. 14, 2020, Trustees of Trfts College. cited by applicant
Nesse, Willem et al. “Increased prevalence of cardiovascular and autoimmune diseases in periodontitis patients: A cross-sectional study.” Journal of periodontology 81, No. 11 (2010): 1622-1628. cited by applicant
Nibali, Luigi et al. “Association between metabolic syndrome and periodontitis: a systematic review and meta-analysis.” The Journal of Clinical Endocrinology & Metabolism 98, No. 3 (2013): 913-920. cited by applicant
Zhou, Xuan et al. “Effects of periodontal treatment on lung function and exacerbation frequency in patients with chronic obstructive pulmonary disease and chronic periodontitis: A 2-year pilot randomized controlled trial.” Journal of clinical periodontology 41, No. 6 (2014): 564-572. cited by applicant
Preshaw, P. M. et al. “Periodontitis and diabetes: a two-way relationship.” Diabetologia 55, No. 1 (2012): 21-31. cited by applicant
Sanz, Mariano et al. “Scientific evidence on the links between periodontal diseases and diabetes: Consensus report and guidelines of the joint workshop on periodontal diseases and diabetes by the International Diabetes Federation and the European Federation of Periodontology.” Diabetes research and clinical practice 137 (2018): 231-241. cited by applicant
Ainamo, J. et al. “Rapid periodontal destruction in adult humans with poorly controlled diabetes A report of 2 cases.” Journal of Clinical Periodontology 17, No. 1 (1990): 22-28. cited by applicant
Seppälä, B. et al. “A site-by-site follow-up study on the effect of controlled versus poorly controlled insulin-dependent diabetes mellitus.” Journal of clinical periodontology 21, No. 3 (1994): 161-165. cited by applicant
Sima, Corneliu et al. “Therapeutic targets for management of periodontitis and diabetes.” Current pharmaceutical design 22, No. 15 (2016): 2216-2237. cited by applicant
Eke, Paul I. et al. “Prevalence of periodontitis in adults in the United States: 2009 and 2010.” Journal of dental research 91, No. 10 (2012): 914-920. cited by applicant
Graves, D. T. et al. “Inflammation and uncoupling as mechanisms of periodontal bone loss.” Journal of dental research 90, No. 2 (2011): 143-153. cited by applicant
Liu, Rongkun et al. “Diabetes enhances periodontal bone loss through enhanced resorption and diminished bone formation.” Journal of dental research 85, No. 6 (2006): 510-514. cited by applicant
Wu, Yi et al. “MicroRNA-126 regulates inflammatory cytokine secretion in human gingival fibroblasts under high glucose via targeting tumor necrosis factor receptor associated factor 6.” Journal of periodontology 88, No. 11 (2017): e179-e187. cited by applicant
Tang, Yin et al. “Porphyromonas endodontalis lipopolysaccharides induce RANKL by mouse osteoblast in a way different from that of Escherichia coli lipopolysaccharide.” Journal of endodontics 37, No. 12 (2011): 1653-1658. cited by applicant
Yin, Xing et al. “Autophagy in bone homeostasis and the onset of osteoporosis.” Bone research 7, No. 1 (2019): 1-16. cited by applicant
Djajadikerta, Alvin et al. “Autophagy induction as a therapeutic strategy for neurodegenerative diseases.” Journal of molecular biology 432, No. 8 (2020): 2799-2821. cited by applicant
Mizushima, Noboru. “Autophagy: process and function.” Genes & development 21, No. 22 (2007): 2861-2873. cited by applicant
Wang, Lei et al. “Netrin-1 regulates ERK1/2 signaling pathway and autophagy activation in wear particle-induced osteoclastogenesis.” Cell Biology International 45, No. 3 (2021): 612-622. cited by applicant
Pierrefite-Carle, Valerie et al. “Autophagy in bone: self-eating to stay in balance.” Ageing Research Reviews 24 (2015): 206-217. cited by applicant
Tong, Xishuai et al. “Osteoprotegerin inhibit osteoclast differentiation and bone resorption by enhancing autophagy via AMPK/mTOR/p70S6K signaling pathway in vitro.” Journal of Cellular Biochemistry 120, No. 2 (2019): 1630-1642. cited by applicant
Boyce, Brendan F. et al. “Functions of RANKL/RANK/OPG in bone modeling and remodeling.” Archives of biochemistry and biophysics 473, No. 2 (2008): 139-146. cited by applicant
Li, Rui-Fang et al. “The adaptor protein p62 is involved in RANKL-induced autophagy and osteoclastogenesis.” Journal of Histochemistry & Cytochemistry 62, No. 12 (2014): 879-888. cited by applicant
Montaseri, Azadeh et al. “The role of autophagy in osteoclast differentiation and bone resorption function.” Biomolecules 10, No. 10 (2020): 1398. cited by applicant
Qiu, Wei et al. “Identification and characterization of a novel adiponectin receptor agonist adipo anti-inflammation agonist and its anti-inflammatory effects in vitro and in vivo.” British journal of pharmacology 178, No. 2 (2021): 280-297. cited by applicant
Li, Ruixue et al. “Effect of GARP on osteogenic differentiation of bone marrow mesenchymal stem cells via the regulation of TGFβ1 in vitro.” PeerJ 7 (2019): e6993. cited by applicant
Chen, Jin-Fei et al. “STAT3-induced IncRNA HAGLROS overexpression contributes to the malignant progression of gastric cancer cells via mTOR signal-mediated inhibition of autophagy.” Molecular cancer 17, No. 1 (2018): 1-16. cited by applicant
Zhang, Yanqing et al. “AdipoRon, the first orally active adiponectin receptor activator, attenuates postischemic myocardial apoptosis through both AMPK-mediated and AMPK-independent signalings.” American Journal of Physiology-Endocrinology and Metabolism 309, No. 3 (2015): E275-E282. cited by applicant
Kim, Yaeni et al. “The adiponectin receptor agonist AdipoRon ameliorates diabetic nephropathy in a model of type 2 diabetes.” Journal of the American Society of Nephrology 29, No. 4 (2018): 1108-1127. cited by applicant
Dikic, Ivan et al. “Mechanism and medical implications of mammalian autophagy.” Nature reviews Molecular cell biology 19, No. 6 (2018): 349-364. cited by applicant
Hansen, Malene et al. “Autophagy as a promoter of longevity: insights from model organisms.” Nature reviews Molecular cell biology 19, No. 9 (2018): 579-593. cited by applicant
Xu, Aimin et al. “Emerging role of autophagy in mediating widespread actions of ADIPOQ/adiponectin.” Autophagy 11, No. 4 (2015): 723-724. cited by applicant
Liu, Ying et al. “Adiponectin stimulates autophagy and reduces oxidative stress to enhance insulin sensitivity during high-fat diet feeding in mice.” Diabetes 64, No. 1 (2015): 36-48. cited by applicant
Ahlstrom, Penny et al. “Adiponectin improves insulin sensitivity via activation of autophagic flux.” Journal of molecular endocrinology 59, No. 4 (2017): 339-350. cited by applicant
Hocking, Lynne J. et al. “Autophagy: a new player in skeletal maintenance?.” Journal of Bone and Mineral Research 27, No. 7 (2012): 1439-1447. cited by applicant
Sanchez, Cheryl P. et al. “Bone growth during rapamycin therapy in young rats.” BMC pediatrics 9, No. 1 (2009): 1-13. cited by applicant
Smink, Jeske J. et al. “Rapamycin inhibits osteoclast formation in giant cell tumor of bone through the C/EBPβ-MafB axis.” Journal of molecular medicine 90, No. 1 (2012): 25-30. cited by applicant
Aderem, Alan et al. “Toll-like receptors in the induction of the innate immune response.” Nature 406, No. 6797 (2000): 782-787. cited by applicant
Alexander, Steve PH et al. “Goals and practicalities of immunoblotting and immunohistochemistry: A guide for submission to the British Journal of Pharmacology.” British journal of pharmacology 175, No. 3 (2018): 407. cited by applicant
Alexander, Steve PH et al. “The Concise Guide to Pharmacology 2019/20: Introduction and other protein targets.” British journal of pharmacology 176 (2019): S1-S20. cited by applicant
Barton, Gregory M. “A calculated response: control of inflammation by the innate immune system.” The Journal of clinical investigation 118, No. 2 (2008): 413-420. cited by applicant
Brochu-Gaudreau, Karine et al. “Adiponectin action from head to toe.” Endocrine 37, No. 1 (2010): 11-32. cited by applicant
Bruce, Clinton R. et al. “The stimulatory effect of globular adiponectin on insulin-stimulated glucose uptake and fatty acid oxidation is impaired in skeletal muscle from obese subjects.” Diabetes 54, No. 11 (2005): 3154-3160. cited by applicant
Cao, Shanjin et al. “The protooncogene c-Maf is an essential transcription factor for IL-10 gene expression in macrophages.” The Journal of Immunology 174, No. 6 (2005): 3484-3492. cited by applicant
Chau, Tieu-Lan et al. “A role for APPL1 in TLR3/4-dependent TBK1 and IKKε activation in macrophages.” The Journal of Immunology 194, No. 8 (2015): 3970-3983. cited by applicant
Chen, Linlin et al. “Inflammatory responses and inflammation-associated diseases in organs.” Oncotarget 9, No. 6 (2018): 7204. cited by applicant
Cheng, Xiang et al. “Adiponectin induces pro-inflammatory programs in human macrophages and CD4+ T cells.” Journal of Biological Chemistry 287, No. 44 (2012): 36896 36904. cited by applicant
Curtis, Michael J. et al. “Experimental design and analysis and their reporting: new guidance for publication in BJP.” British journal of pharmacology 172, No. 14 (2015): 3461. cited by applicant

edspgr.11655212