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KDDF-201601-01 Development of gut-restricted farnesoid X receptor (FXR) modulators as type II antidiabetics(Metabolic Disorders, Chemical) [09.01.2016]

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Development and Market Objectives

Researchers in Salk Institute have recently shown that fexaramine (Fex) is a non-systemic FXR agonist to mimic food activation of intestinal FXR, resulting in intestinally-restricted FXR activation. Fex treatment produced a novel metabolic profile that includes reduced weight gain, decreased inflammation, browning of white adipose tissue, and increased insulin sensitization (Fang et al, Nature Medicine, 159-165, 2015).

In the subsequent studies, they demonstrated that Fex enhances GLP-1 secretion in L cells, leading to improve insulin secretion in response to glucose. Concomitantly, Fex also increases expression of GLP-1R in pancreatic β cell to enhance glucose-stimulated insulin secretion. Furthermore, a Fex analog, Fex-D remarkably improved metabolic parameters with relatively low dosage and shorter treatment period (WO 2015/138969 A1). The beneficial efficacy achieved with Fex and its analog, Fex-D suggests intestinal FXR activation as a promising and potentially safer approach in the treatment of insulin resistance and type II diabetes.

 

On the basis of these findings, we planned to develop novel gut-restricted FXR modulators to examine if they are more efficacious in controlling glycemia and reducing body weight in obese and diabetic rodent models.

Unmet Medical Need & Target Patients

Since the weight-reducing effect of GLP-1 agonists and SGLT-2 inhibitors is attributed to the either limited food intake or heavy glycosuria (up to 119 g per day, corresponding to 476 kilocalories), they could decrease the patients’ quality of life significantly in the long-term treatment period. Chronic GLP-1 receptor activation by GLP-1 agonist in human might lead to pancreatitis, pancreatic cancer, or thyroid cancer. Currently, these safety concerns remain debated, a black box warning is now provided with prescription information for both liraglutide and exenatide by US FDA.

 

Heavy glycosuria and dehydration caused by the SGLT-2 inhibitors are associated with a number of adverse effects that include tiredness, hypotension, impairment in renal function, genital mycotic infections, low urinary tract infections, diabetic acidosis, and bone fracture. In addition to this, the SGLT-2 inhibitors are prohibited to be used in the subset of type 2 diabetes patients with severe renal impairment, end-stage renal disease, or on dialysis.

 

Analyses of epidemiology and market trends in type 2 diabetes and efficacies and adverse effects of commercially available type 2 antidiabetics suggest us that a new class of antidiabetics that might be able to control both blood glucose level and body weight without affecting food intake and glucose excretion, while enhancing energy expenditure, is highly promising in future market. In addition to this, if a new class of antidiabetics is gut-restricted, it might show much lower adverse effects by minimal systemic exposure, compared with commercially available type 2 antidiabetics.

Status

Design, synthesis, and biological evaluation of lead compounds of gut-restricted FXR modulators as potential antidiabetic agent, to develop a preclinical candidate and a backup compound.

 

  1. 1. We are optimizing the structures of Fex and Fex-D to screen more efficacious compounds than Fex-D

  2. 2. Based on reporter assay, we will determine if each compound works as FXR agonist or antagonist in vitro. Once we obtain the compounds, we will demonstrate that the compounds are FXR specific modulators by nuclear hormone receptor selectivity test.

  3. 3. To examine whether our modulators are gut-restricted, we will deliver our modulators in different doses and examine FXR target gene expression profile in the intestinal tract and the liver. We will calculate the maximal dose of our modulators without induction of hepatic FXR target genes.

  4. 4. We will test our two selected compounds in two different animal models, diet-induced obese mice and ob/ob mice.

Intellectual Property

In preparation

Competitive Advantages

Indication

Metabolic Disorder

Research Period

2016.7.15-2017.7.14

Company

Ewha Womans University, College of Pharmacy

Developmental Stage

Optimization

Additional Information

Contact Information

Contact
Address Company Name: Ewha Womans University, College of Pharmacy
WebSite Homepage: http:// Contact Person: Dae-Kee Kim
E-mail: dkkim@ewha.ac.kr Contact: +82-2-3277-3025

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