GLP-1 small molecule with cardiovascular benefits

Abstract

The invention provides a GLP-1 small molecule compound with cardiovascular benefits, which not only can be used for treatment of diabetes mellitus, but also can be independently or jointly applied as a cardiovascular protective agent and has the pharmaceutical application of reducing cardiovascular adverse events or reducing cardiovascular adverse events in type 2 diabetes mellitus. The reduction of cardiovascular adverse events comprises reduction of the incidence rate of myocardial infarction of patients, reduction of the hospitalization frequency caused by heart failure, reduction of the risk of myocardial infarction and stroke of patients, and reduction of the cardiovascular death risk of heart failure of adults with reduced ejection fraction and the hospitalization risk caused by heart failure (NYHA II-IV level).

Description

Background technique [0001] Cardiovascular disease is the main cause of morbidity and mortality in patients with type 2 diabetes. As more and more diabetes drugs are brought to the market, concerns have arisen about the impact of these drugs on cardiovascular risk, especially with the drug rosiglitazone, which has been associated with a significant increase in the risk of myocardial infarction. With these concerns in mind, in 2008 the FDA issued a recommendation that new diabetes-lowering drugs should not increase the risk of cardiovascular disease. Jardiance (empagliflozin, SGLT-2 inhibitor) is the first hypoglycemic drug that has shown cardiovascular benefits in clinical practice. It was expanded and approved by the FDA on December 2, 2016 for new indications for reducing type 2 Risk of cardiovascular death in patients with diabetes. [0002] Among GLP-1 therapeutic agents, it was initially thought that GLP-1 primarily affects insulin release. However, it has been found t...

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[0004] However, not all GLP-1 can show cardiovascular benefits, Sheahan KH, et al. PostgradMed J2020; 96: 156-161 reported that Lixisenatide only showed non-inferiority to placebo in a clinical trial of 6068 patients In the clinical trial of 9,340 patients, Liraglutide was the first GLP-1 agonist to show cardiovascular benefits better than placebo. In the clinical trial of 3,297 patients, Semaglutide There was no significant difference between placebo and placebo in sudden cardiac death or non-fatal myocardial infarction. In the clinical trial of Albiglutide in 9463 patients, the main composite cardiovascular endpoint of Albiglutide group occurred in 7% of patients, while the placebo group This ratio is 9%, and there is a significant difference between the two. In a clinical trial of 9901 patients, dulaglutide had a significant difference in non-fatal stroke (2.7% vs 3.5%, p=0.017), oral Semaglutide showed no significant difference in cardiovascular benefits in a clinical trial of 3183 patients

[0005] Moreover, the GLP-1 mentioned above are all macromolecular polypeptide drugs, and there is no GLP-1 small molecule drug on the market. Small molecules in the clinical research stage such as TTP-OAD2, TTP273, PF-06882961, OWL833 (LY-3502970), TTP273 is in clinical phase II, OWL833 is in clinical phase I, and no reports of cardiovascular benefits have been seen so far, while the clinical phase I data of PF-06882961 show that 3-240 mg per day has mild to moderate effects on the heart Lesions, moderate to severe effects on the thymus (helps control infection), moderate to moderate gastric ulceration in rats given the highest dose, also reported in Molecular Cell80, 1-16, November 5, 2020, PF- 06882961, but not CHU-128, was able to mimic the agonism of the GLP-1 protein, in contrast to PF-06882961 which was active in all assays (30- to 100-fold less potent than GLP-1 concentrations), Shows maximal internalization similar to GLP-1, but only partial agonism in pERK1 / 2, calcium mobilization, and β-arrestin recruitment, i.e. PF-06882961 shows glucagon-like peptide similar to GLP-1 TTP-OAD2 and OWL833 show similar signaling and regulatory properties, including promoting the recruitment or internalization of β-arrestin, but are very poor for pERK1 / 2 and calcium mobilization Agonism, even as reported, PF-06882961 still has mild to moderate cardiac damage as described in phase I data

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