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KDDF-201306-07 Development of HD-6277, a potent GPR40 agonist without hypoglycemic risk(Metabolic Disorders, Chemical) [10.07.2013]

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Development and Market Objectives

Our objective is to develop HD-6277, a competitive therapeutic GPR40 agonist for the control of hypoglycemia, and generate the API for preclinical research.

Unmet Medical Need & Target Patients

Type II diabetes mellitus is a widespread chronic disease. In 2010, 6.4% of the adult population was afflicted, and is projected to reach 7.7% by 2030, according to experts (Diabetes Research and Clinical Practice, 2010; Diabetes Care, 2004). The Korean domestic situation is more serious; the morbidity rate of the disease in 2009 was 9.9% of for 30~70 year old adults (Diabetes Metab. J., 2011).

Commonly-used therapeutics for type II diabetes mellitus such as metformin, sulfonylurea, and rosiglitazone cause many adverse effects including diarrhea, stomach aches, hypoglycemic induction, weight increases and cardiovascular disorders. In addition, the long-term administration of sulfonylurea creates additional clinical issues, and type II diabetes typically requires long term administration of drugs for treatment.

The islet beta-cell secretion capacity for insulin in most patients is often found to be decreased by more than 50% upon initial medical examination. This beta-cell secretion capacity of insulin, as well as the total number of beta-cells continues to decrease over time. Another drawback of sulfonylurea therapy is that it renders glycemic control difficult despite its effects on beta-cells. Currently, incretine hormone-based drugs that regulate blood glucose and protect beta-cells are being developed. However, evidence for real clinical effects on blood sugar levels and beta-cells over prolonged periods of time are needed in order for them to remain relevant when compared to metformin or sulfonylurea therapy.

Status

GPR40 (G-protein-coupled receptor 40) is a membrane protein that develops in islet cells of the small and large intestine. GPR40 activation in islet beta-cells by GPR40 agonists is known to stimulate insulin secretion (Gromada J., 2006). Hyundai Pharmacy has created a lead backbone from a large number of chemical modifications and generated hundreds of new compounds. Each lead backbone-based compound has passed the primary screening process by in vitro methods, based on GPR40 agonist mechanism of action.  Compound HD-6277 was identified to be the safest after 2nd round in vivo screening using normal and diabetic rodent models.

HD-6277, a potent GPR40 agonist, has demonstrated its superiority and safety in PK profiling through cutting-edge research. The compound is highly effective for blood glucose control in a number of type II diabetes mellitus animal models with 2~4 week interval repeated administration and has shown excellent safety characteristics in non-GLP 2-week repeating toxicity tests. In addition, we have confirmed the outstanding HD-6277 bioavailability and safety in both rodents and non-rodent animal models and confirmed that there are no side effects such as hypoglycemia after repeated administration for 4 weeks. We are currently conducting additional research to consolidate its future superiority in the market and developing the HD-6277 API for GLP safety evaluation

Intellectual Property

Hyundai Pharmacy has developed a unique scaffold and a GPR40 agonist library through the creation of hundreds of new compounds based on lead frames. A patent application is present in STN search, Registry database and the Marpat database. 

Application Number: 10-2013-0043100
Application Date: 2013.4.13
Name:
(Korean) 신규한 사이클로헥센 유도체, 이의 약학적으로 허용 가능한 염 또는 이의 광학 이성질체, 이의 제조방법 및 이를 유효성분으로 함유하는 대사성 질환 예방 또는 치료용 약학적 조성물
(English) Novel cyclohexene derivative, pharmaceutically acceptable salts thereof or optical isomer thereof, preparation method thereof and pharmaceutical composition for prevention or treatment of the metabolic diseases containing the same as an active ingredient
 

Competitive Advantages

The mechanism of action of GPR40 agonists that target beta-cells is deeply related to blood glucose control and the fact that such agonists stimulate insulin secretion causing a drop in blood sugar levels to a greater extent than sulfonylurea (Lin DCH., 2011). Of particular note, GPR agonists are not only effective in potently downregulating blood sugar levels strongly, they can also counteract hypoglycemia because it has been shown that insulin secretion of beta-cells stimulated by GPR40 agonists only occurs during times of high blood sugar levels. Additionally, activation of GPR40 in L-cells spreads from the small and large intestine via cognate GLP-1 (glucagon-like peptide-1) secretion which is known to affect hypoglycemia. This protects beta-cells and has an effect on weight gain, so it is possible that GPR40 agonists can act to prevent deterioration of beta-cells in diabetic patients and provide a mechanism for control of weight gain (Luo J, 2012). HD-6277 has demonstrated an outstanding potential for glycemic control in diabetic animal models using Fasiglifam as a comparator, and GLP-1 secretion in the blood was increased with HD-6277 administration. Based on these research results, further experiments that will verify the possibility of anti-apoptotic effects in beta-cells and stimulation of neogenesis will be conducted. In addition, incretin’s potency will be verified by confirming the blood sugar reduction ratios after food intake in relation to stable hypoglycemic capacity. Moreover, the practicality and safety of co-administration with HD-6277 will be confirmed via in vivo analysis of the metabolome. 

Indication

Metabolic Disorders

Research Period

Oct. 01, 2013-Dec. 31, 2014

Company

Hyundai Pharm.

Developmental Stage

Lead Optimization

Additional Information

Contact Information

Contact
Address Company Name: Hyundai Pharm.
WebSite Homepage: http://www.hyundaipharm.co.kr Contact Person: Dae-hoon Kim
E-mail: 20100083@hdpharm.co.kr Contact: +82-31-284-2031

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