IP Library › Granted Patent US 12,497,382
Granted Patent B2
US 12,497,382 · App. 18/195,767 · Granted Dec 16, 2025

GLP-1R modulating compounds

Inventors: Stephen E. Ammann (Redwood City, CA); Gediminas J. Brizgys (San Carlos, CA); James S. Cassidy (Foster City, CA); Elbert Chin (San Mateo, CA); Chienhung Chou (Dublin, CA); Jeromy J. Cottell (Redwood City, CA); Michael Graupe (Pacifica, CA); Chao-I Hung (Foster City, CA); Kavoos Kolahdouzan (San Francisco, CA); Scott D. Schroeder (Union City, CA); Nathan D. Shapiro (Belmont, CA); Daniel G. Shore (Redwood City, CA); Suzanne M. Szewczyk (San Mateo, CA); James G. Taylor (Burlingame, CA); Rhiannon Thomas-Tran (San Jose, CA); Nathan E. Wright (Foster City, CA); Zheng-Yu Yang (Palo Alto, CA); Sheila M. Zipfel (San Mateo, CA)
Assignee: Gilead Sciences, Inc.
C07D401/14A61K31/4439A61K31/506A61K45/06C07D235/16C07D401/10C07D403/06C07D405/14C07D409/14C07D413/14C07D417/14C07D471/04C07D493/08
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Quick Facts
Patent No.
US 12,497,382
App. No.
18/195,767
Granted
Dec 16, 2025
Kind
B2
Abstract

The present disclosure provides GLP-1R agonists, and compositions, methods, and kits thereof. Such compounds are generally useful for treating a GLP-1R mediated disease or condition in a human.

Claims (10)

1 . A method of treating a GLP-1R mediated disease or condition comprising administering to a subject in need thereof a pharmaceutically effective amount of a compound, or pharmaceutically acceptable salt thereof, wherein the compound has the structure:

2 . The method of claim 1 , wherein the disease or condition comprises a liver disease.

3 . The method of claim 2 , wherein the disease or condition comprises liver fibrosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver cirrhosis, compensated liver fibrosis, decompensated liver fibrosis, hepatocellular carcinoma, Primary Biliary Cirrhosis (PBC), or Primary Sclerosing Choleangitis (PSC).

4 . The method of claim 3 , wherein the disease or condition comprises non-alcoholic fatty liver disease (NAFLD).

5 . The method of claim 3 , wherein the disease or condition comprises non-alcoholic steatohepatitis (NASH).

6 . The method of claim 1 , wherein the disease or condition comprises a metabolic disease.

7 . The method of claim 1 , wherein the disease or condition comprises type 1 diabetes, type 2 diabetes, pre-diabetes, idiopathic type 1 diabetes, latent autoimmune diabetes, maturity onset diabetes of the young, early onset diabetes, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease, diabetic retinopathy, adipocyte dysfunction, visceral adipose deposition, obesity, eating disorders, sleep apnea, weight gain, sugar craving, dyslipidemia, hyperinsulinemia, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, post-prandial lipemia, metabolic acidosis, ketosis, arthritis, left ventricular hypertrophy, Parkinson's Disease, peripheral arterial disease, macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, angina pectoris, premenstrual syndrome, thrombosis, atherosclerosis, impaired glucose metabolism, vascular restenosis, dementia, or Alzheimer's disease.

8 . The method of claim 1 , wherein the compound or pharmaceutically acceptable salt thereof is administered in combination with an additional therapeutic agent.

9 . The method of claim 8 , wherein the additional therapeutic agent is selected from the group consisting of: peptide YY or an analogue thereof, a neuropeptide Y receptor type 2 (NPYR2) agonist, a NPYR1 agonist, an NPYR5 antagonist, a cannabinoid receptor type 1 (CB1 R) antagonist, a lipase inhibitor, orlistat, a human proislet peptide (HIP), a melanocortin receptor 4 agonist (MC4R), setmelanotide, a melanin concentrating hormone receptor 1 antagonist, a famesoid X receptor (FXR) agonist, obeticholic acid, apoptotic signal-regulating kinase (ASK-1) inhibitor, zonisamide, phentermine alone or in combination with topiramate, a norepinephrine/dopamine reuptake inhibitor, buproprion, an opioid receptor antagonist, naltrexone, a combination of norepinephrine/dopamine reuptake inhibitor and opioid receptor antagonist, a combination of bupropion and naltrexone, a GDF-15 analog, sibutramine, a cholecystokinin agonist, amylin and analogues thereof, pramlintide, leptin and analogues thereof, metroleptin, a serotonergic agent, lorcaserin, a methionine aminopeptidase 2 (MetAP2) inhibitor, beloranib, ZGN-1061, phendimetrazine, diethylpropion, benzphetamine, an SGLT2 inhibitor, empagliflozin, canagliflozin, dapagliflozin, ipragliflozin, tofogliflozin, sergliflozin etabonate, remogliflozin etabonate, ertugliflozin, an SGLTL1 inhibitor, a dual SGLT2/SGLT1 inhibitor, a fibroblast growth factor receptor (FGFR) modulator, an AMP-activated protein kinase (AMPK) activator, biotin, a MAS receptor modulator, a glucagon receptor agonist alone or in combination with another GLP-1 R agonist, liraglutide, exenatide, dulaglutide, albiglutide, lixisenatide, semaglutide, a peroxisome proliferator-activated receptor alpha (PPARα) agonist, fish oil, an acetyl-coA carboxylase (ACC) inhibitor, a TGFβ antagonist, GFRAL agonist, and a pharmaceutically acceptable salt thereof.

10 . The method of claim 1 , wherein the compound has the structure:

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 17, 2023
From: AMMANN, STEPHEN E.; BRIZGYS, GEDIMINAS J.; CASSIDY, JAMES S.; CHIN, ELBERT; CHOU, CHIENHUNG; COTTELL, JEROMY J.; GRAUPE, MICHAEL; HUNG, CHAO-I; KOLAHDOUZAN, KAVOOS; SCHROEDER, SCOTT D.; SHAPIRO, NATHAN D.; SHORE, DANIEL G.; SZEWCZYK, SUZANNE M.; TAYLOR, JAMES G.; THOMAS-TRAN, RHIANNON; WRIGHT, NATHAN E.; YANG, ZHENG-YU; ZIPFEL, SHEILA M.
To: GILEAD SCIENCES, INC.
Reel/Frame 064287/0608 →
Continuity (4)
Continuation 17077729 · Oct 22, 2020
Provisional Application 63028187 · May 21, 2020
Provisional Application 62926270 · Oct 25, 2019
Related Publication 20230391747A1 · Dec 7, 2023
References Cited (151)
US 8957073B2 · Allen · 2015 [cited by applicant]
US 10543212B2 · Matsunaga et al. · 2020 [cited by applicant]
US 10954221B2 · Zhong et al. · 2021 [cited by applicant]
US 11702404B2 · Ammann et al. · 2023 [cited by applicant]
US 11851419B2 · Brizgys · 2023 [cited by applicant]
US 11858918B2 · Armstrong · 2024 [cited by applicant]
US 11981666B2 · Zhai · 2024 [cited by applicant]
US 12091404B2 · Brizgys · 2024 [cited by applicant]
US 12121511B2 · Ammann · 2024 [cited by applicant]
US 20170035881A1 · Lannutti et al. · 2017 [cited by applicant]
US 20180170908A1 · Aspnes et al. · 2018 [cited by applicant]
US 20200325121A1 · Zhong et al. · 2020 [cited by applicant]
US 20210023072A1 · Freeman et al. · 2021 [cited by applicant]
US 20210171499A1 · Ammann · 2021 [cited by applicant]
US 20220177449A1 · Brizgys et al. · 2022 [cited by applicant]
US 20220288030A1 · Ammann et al. · 2022 [cited by applicant]
US 20220298148A1 · Brizgys et al. · 2022 [cited by applicant]
US 20220306614A1 · Brizgys et al. · 2022 [cited by applicant]
US 20230021705A1 · Armstrong et al. · 2023 [cited by applicant]
US 20240199580A1 · Brizgys · 2024 [cited by applicant]
US 20240199589A1 · Armstrong · 2024 [cited by applicant]
US 20250084072A1 · Brizgys · 2025 [cited by applicant]
US 20250099431A1 · Ammann · 2025 [cited by applicant]
CN 112409331A · 2021 [cited by applicant]
CN 113480534A · 2021 [cited by applicant]
CN 113493447A · 2021 [cited by applicant]
CN 113816948A · 2021 [cited by applicant]
EP 3438095A1 · 2019 [cited by applicant]
EP 4057055A1 · 2022 [cited by applicant]
TW 201904959A · 2019 [cited by applicant]
TW 202015683A · 2020 [cited by applicant]
WO WO200008015A2 · 2000 [cited by applicant]
WO 2001002369A1 · 2001 [cited by applicant]
WO WO2003026587A2 · 2003 [cited by applicant]
WO WO2004099192A2 · 2004 [cited by applicant]
WO 2004108672A1 · 2004 [cited by applicant]
WO WO2005014543A1 · 2005 [cited by applicant]
WO WO2006055708A2 · 2006 [cited by applicant]
WO WO2006066879A2 · 2006 [cited by applicant]
WO WO2007031791A1 · 2007 [cited by applicant]
WO WO2007115077A2 · 2007 [cited by applicant]
WO WO2008033455A2 · 2008 [cited by applicant]
WO 2009111700 · 2009 [cited by applicant]
WO WO2010029299A1 · 2010 [cited by applicant]
WO WO2010029300A1 · 2010 [cited by applicant]
WO WO2010046780A2 · 2010 [cited by applicant]
WO 2011143365 · 2011 [cited by applicant]
WO 2011156655 · 2011 [cited by applicant]
WO WO2011163355A1 · 2011 [cited by applicant]
WO WO2013025733A1 · 2013 [cited by applicant]
WO WO2013056679A1 · 2013 [cited by applicant]
WO 2013090454 · 2013 [cited by applicant]
WO WO2013186229A1 · 2013 [cited by applicant]
WO WO2016018701A1 · 2016 [cited by applicant]
WO WO2016089060A2 · 2016 [cited by applicant]
WO WO2016118638A1 · 2016 [cited by applicant]
WO WO2017161028A1 · 2017 [cited by applicant]
WO WO2018109607A1 · 2018 [cited by applicant]
WO WO2018183112A1 · 2018 [cited by applicant]
WO WO2019055540A1 · 2019 [cited by applicant]
WO WO2019239319A1 · 2019 [cited by applicant]
WO WO2019239371A1 · 2019 [cited by applicant]
WO WO2020033413A2 · 2020 [cited by applicant]
WO WO2020103815A1 · 2020 [cited by applicant]
WO WO2020207474A1 · 2020 [cited by applicant]
WO WO2020263695A1 · 2020 [cited by applicant]
WO WO2021018023A1 · 2021 [cited by applicant]
WO WO2021018026A1 · 2021 [cited by applicant]
WO WO2021081207A1 · 2021 [cited by applicant]
WO WO2021096284A1 · 2021 [cited by applicant]
WO WO2021096304A1 · 2021 [cited by applicant]
WO WO2021112538A1 · 2021 [cited by applicant]
WO WO2021154796A1 · 2021 [cited by applicant]
WO WO2021155841A1 · 2021 [cited by applicant]
WO WO2021160127A1 · 2021 [cited by applicant]
WO WO2021187886A1 · 2021 [cited by applicant]
WO WO2021191812A1 · 2021 [cited by applicant]
WO WO2021197464A1 · 2021 [cited by applicant]
WO WO2021242817A1 · 2021 [cited by applicant]
WO WO2021244645A1 · 2021 [cited by applicant]
WO 2022031994A1 · 2022 [cited by applicant]
WO WO2022040600A1 · 2022 [cited by applicant]
WO WO2022068772A1 · 2022 [cited by applicant]
WO WO2022078152A1 · 2022 [cited by applicant]
WO WO2022109182A1 · 2022 [cited by applicant]
WO WO2022111624A1 · 2022 [cited by applicant]
WO 2022189191 · 2022 [cited by applicant]
WO WO2022192428A1 · 2022 [cited by applicant]
WO WO2022192430A1 · 2022 [cited by applicant]
WO 2022216094A1 · 2022 [cited by applicant]
WO 2022224164 · 2022 [cited by applicant]
WO WO2022225914A1 · 2022 [cited by applicant]
WO WO2022225941A1 · 2022 [cited by applicant]
WO 2023102378 · 2023 [cited by applicant]
Ratziu et al., Journal of Hepatology, 2015, vol. 62, pp. S65-S75. (Year: 2015). [cited by examiner]
Andersen, A et al. (2018), “Glucagon-like peptide 1 in health and disease”, Nat Rev Endocrinol., Jul;14(7):390-403. [cited by applicant]
Armstrong M J et al. (2016), “Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study”, Lancet, 387(10019):679-690. [cited by applicant]
Armstrong, M et al. (2013), “Liraglutide efficacy and action in non-alcoholic steatohepatitis (LEAN): study protocol for a phase II multicentre, double-blinded, randomised, controlled trial”, BMJ Open., 3(11):e003995, p… [cited by applicant]
Armstrong, M J et al. (2016), “Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatohepatitis”, Randomized Controlled Trial J Hepatol., 64(2):399-408. [cited by applicant]
Armstrong, M. J. (2017), “Glucagon-like peptide-1 analogues in nonalcoholic steatohepatitis: From bench to bedside”, Review Clin Liver Dis (Hoboken), 10(2):32-35. [cited by applicant]
Ben-Shlomo, S et al. (2011), “Glucagon-like peptide-1 reduces hepatic lipogenesis via activation of AMP-activated protein kinase”, J Hepatol. 54(6):1214-23. [cited by applicant]
Bernsmeier, C et al. (2014), “Glucose-Induced Glucagon-Like Peptide 1 Secretion Is Deficient in Patients with Non-Alcoholic Fatty Liver Disease”, PLoS One, 9(1):e87488, 1-7. [cited by applicant]
Bueno, A B et al. (2016), “Positive Allosteric Modulation of the Glucagon-like Peptide-1 Receptor by Diverse Electrophiles”, J Biol Chem, May 13, 2016; 291(20):10700-15. [cited by applicant]
Carbone L J et al. (2016), “Incretin-based therapies for the treatment of non-alcoholic fatty liver disease: A systemic review and meta-analysis”, J Gastroenterol Hepatol, 31(1):23-31. [cited by applicant]
Chen D et al. (2007), “A nonpeptidic agonist of glucagon-like peptide 1 receptors with efficacy in diabetic db/db mice”, Proc Natl Acad Sci USA, 104(3):943-948. [cited by applicant]
Chen, J et al. (2017), “GLP-1/GLP-1R Signaling in Regulation of Adipocyte Differentiation and Lipogenesis”, Cell Physiol Biochem, 42(3):1165-1176. [cited by applicant]
Dalsgaard N B et al. (2018), “Effects of glucagon-like peptide-1 receptor agonists on cardiovascular risk factors: A narrative review of head-to-head comparisons”, Diabetes Obes Metab, 20(3):508-519. [cited by applicant]
Davies, M et al. (2017), “Effect of Oral Semaglutide Compared With Placebo and Subcutaneous Semaglutide on Glycemic Control in Patients With Type 2 Diabetes: A Randomized Clinical Trial”, JAMA, 318(15):1460-1470. [cited by applicant]
De Graaf C et al. (2016), “Glucagon-Like Peptide-1 and Its Class B G Protein-Coupled Receptors: A Long March to Therapeutic Successes”, Pharmacol Rev., 68(4):954-1013. [cited by applicant]
Donnelly K L et al. (2005), “Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease”, J Clin Invest, 115(5):1343-1351. [cited by applicant]
Edmonds, D J et al. (2013), “Oral GLP-1 Modulators for the Treatment of Diabetes”, Annual Reports in Medicinal Chemistry, Chapter Nine, 48:119-130. [cited by applicant]
Eguchi Y et al. (2015), “Pilot study of liraglutide effects in non-alcoholic steatohepatitis and non-alcoholic fatty liver disease with glucose intolerance in Japanese patients (LEAN-J)”, Hepatol Res, 45(3):269-278. [cited by applicant]
Gastaldelli A et al. (2016), “Exenatide improves both hepatic and adipose tissue insulin resistance: A dynamic positron emission tomography study”, Hepatology, 64(6):2028-2037. [cited by applicant]
Intl. Search Report—Written Opinion dated Jan. 21, 2021 for Intl. Appl. No. PCT/US2020/056867. [cited by applicant]
Jazayeri A et al. (2017), “Crystal structure of the GLP-1 receptor bound to a peptide agonist”, Nature, 546(7657):254-258. [cited by applicant]
Jones, B et al. (2018), “Targeting GLP-1 receptor trafficking to improve agonist efficacy”, Nature Communications, 9:1602, pp. 1-17. [cited by applicant]
Knudsen, L B et al. (2007), “Small-molecule agonists for the glucagon-like peptide 1 receptor”, Proc Natl Acad Sci USA, 104(3):937-942. [cited by applicant]
Koole C et al. (2013), “Recent advances in understanding GLP-1R (glucagon-like peptide-1 receptor) function”, Biochem Soc Trans, 41(1):172-179. [cited by applicant]
Ma H et al. (2020), “Structural insights into the activation of GLP-1R by a small molecule agonist”, Cell Res 30, 1140-1142. [cited by applicant]
Mendez M et al. (2019), “Design, Synthesis and Pharmacological Evaluation of Potent Positive Allosteric Modulators of the Glucagon-like Peptide-1 Receptor (GLP-1R)”, J. Med. Chem., Just Accepted Manuscript, Publication … [cited by applicant]
Nauck, M A et al. (2011), “Rapid tachyphylaxis of the glucagon-like peptide 1-induced deceleration of gastric emptying in humans”, Diabetes, 60(5):1561-1565. [cited by applicant]
Nauck, M A et al. (2016), “A Phase 2, Randomized, Dose-Finding Study of the Novel Once-Weekly Human GLP-1 Analog, Semaglutide, Compared With Placebo and Open-Label Liraglutide in Patients With Type 2 Diabetes”, Diabetes… [cited by applicant]
Petit, J-M et al. (2017), “GLP-1 receptor agonists in NAFLD”, Diabetes Metab., 43 Suppl 1:2S28-2S33. [cited by applicant]
Plisson F et al. (2017), “Helixconstraints and amino acid substitution in GLP-1 increase CAMP and insulin secretion but not beta-arrestin 2 signaling”, Eur J Med Chem, 127:703-714. [cited by applicant]
Portillo-Sanchez P et al. (2016), “Treatment of Nonalcoholic Fatty Liver Disease (NAFLD) in patients with Type 2 Diabetes Mellitus”, Clin Diabetes Endocrinol, 2:9. [cited by applicant]
Sloop K W et al. (2010), “Novel small molecule glucagon-like peptide-1 receptor agonist stimulates insulin secretion in rodents and from human islets”, Diabetes, 59(12):3099-3107. [cited by applicant]
Song G et al. (2017), “Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators”, Nature, 546(7657):312-315. [cited by applicant]
Svegliati-Baroni G et al. (2011), “Glucagon-like peptide-1 receptor activation stimulates hepatic lipid oxidation and restores hepatic signalling alteration induced by a high-fat diet in nonalcoholic steatohepatitis”, L… [cited by applicant]
Takayanagi R et al. (2018), “Evaluation of Drug Efficacy of GLP-1 Receptor Agonists and DPP-4 Inhibitors Based on Target Molecular Binding Occupancy”, Biol Pharm Bull, 41(2):153-157. [cited by applicant]
Tong W et al. (2016), “Liraglutide ameliorates non-alcoholic fatty liver disease by enhancing mitochondrial architecture and promoting autophagy through the SIRT1/SIRT3-FOXO3a pathway”, Hepatol Res., 46(9):933-943. [cited by applicant]
Umapathysivam M M et al. (2014), “Comparative effects of prolonged and intermittent stimulation of the glucagon-like peptide 1 receptor on gastric emptying and glycemia”, Diabetes, 63(2):785-790. [cited by applicant]
Vendrell J et al. (2011), “Study of the potential association of adipose tissue GLP-1 receptor with obesity and insulin resistance”, Endocrinology, 152(11):4072-4079. [cited by applicant]
Vilar-Gomez E et al. (2015), “Weight Loss Through Lifestyle Modification Significantly Reduces Features of Nonalcoholic Steatohepatitis”, Gastroenterology, 149(2):367-378.e5. [cited by applicant]
Villanueva-Penacarrillo M L et al. (2001), “Effect of GLP-1 on lipid metabolism in human adipocytes”, Horm Metab Res, 33(2):73-77. [cited by applicant]
VTv Therapeutics (2016), “Oral Small Molecule GLP-1 Receptor (GLP-1R) Agonists for Type 2 Diabetes (T2DM) with Negligible Nausea and Vomiting”, Presentation from Keystone Symposia 2016. [cited by applicant]
Wang X-C et al. (2014), “Effects of glucagon-like peptide-1 receptor agonists on non-alcoholic fatty liver disease and inflammation”, World J Gastroenterol, 20(40):14821-14830. [cited by applicant]
Wootten D et al. (2013), “Differential activation and modulation of the glucagon-like peptide-1 receptor by small molecule ligands”, Mol Pharmacol, 83(4):822-834. [cited by applicant]
Wootten D et al. (2016), “A Hydrogen-Bonded Polar Network in the Core of the Glucagon-Like Peptide-1 Receptor Is a Fulcrum for Biased Agonism: Lessons from Class B Crystal Structures”, Mol Pharmacol, 89(3):335-347. [cited by applicant]
Yang D et al. (2015), “Landmark studies on the glucagon subfamily of GPCRs: from small molecule modulators to a crystal structure”, Acta Pharmacol Sin, 36(9):1033-42. [cited by applicant]
Intl. Preliminary Report on Patentability dated May 5, 2022 for Intl. Appl. No. PCT/US2020/056867. [cited by applicant]
Examination Report dated Aug. 25, 2022 for Indian Appl. No. 202217023266. [cited by applicant]
Notice of Opposition dated Sep. 8, 2022 for Colombian Appl. No. NC2022/0005077. [cited by applicant]
Notice of Allowance dated Sep. 26, 2022 for Taiwanese Appl. No. 109136833. [cited by applicant]
Examination Report dated Sep. 27, 2021 for Gulf Cooperation Council Appl. No. 40714. [cited by applicant]
Office Action dated Dec. 27, 2021 for Taiwanese Appl. No. 109136833. [cited by applicant]
Office Action dated Mar. 8, 2023 Australia Application No. 2020369568. [cited by applicant]
Office Action of May 8, 2023 for Japan Application No. 2022-523351. [cited by applicant]
Office Action of May 11, 2023 for Canada Application No. 3157525. [cited by applicant]
Office Action of Jun. 13, 2023 for Malaysia Application No. PI2022002017. [cited by applicant]
N. Foloppe, Potter, Bioorganic & Medicinal Chemistry, 2006, 14, 1792-1804. [cited by applicant]
Office Action and Search Report AP No. AP/P/2023/015172 Oct. 12, 2024. [cited by applicant]