Ligand’s Metabolic Pathway Drug Discovery Programs
Designing small molecules with special chemistry technology have led to the development of lead compounds that contain unique functional groups resulting desirable tissue-selectivity profiles to avoid potential side-effects. For example, HepDirect is a Ligand proprietary technology to significantly increase the active compound exposure in the liver without significant effect in circulation.
Prevalence of diabetes mellitus and obesity has been increasing at an alarming rate despite the availability of many medications and the advance of medical science. Ligand metabolic pathway programs offer unique opportunities to address the unmet medical needs and include Glucagon Receptor (GCGR) Antagonist (Pre-Clinical), Fructose-1,6-bisphosphatase (FBPase) Inhibitor (Phase-II), Liver-Specific Glucokinase Activator (GKA) (Research), and Enterocyte-Directed DGAT-1 Inhibitor (Research) Programs.
GCGR Antagonist Program for Type 2 Diabetes Mellitus (T2DM)
GCGR controls biological activity of glucagon that counteracts glucose lowering effect of insulin as part of glucose homeostasis control. Selectively antagonizing GCGR to lower glucose can be an effective alternative strategy of glucose management for T2DM patients who have inappropriately elevated glucagon levels. The candidate compound, LGD-6972 (formally MB11262), has demonstrated significant and consistent glucose lowering activity and a desirable safety profile in animal models. LGD-6972 has a unique chemical structure that offers a desirable drug-property, and is currently in pre-clinical development.
Liver-Specific GKA Program for T2DM
Glucokinase (GKA) is an enzyme that facilitates removal of glucose in circulation and functions as a glucose sensor mainly in the liver and pancreas cells. GKAs have been shown as an effective strategy to lower glucose in animal models and patients with T2DM. By selectively activating the enzymatic activity in the liver, a liver-specific GKA can significantly reduce the risk of hypoglycemia that was observed with earlier generation of GKAs. Taking advantage of the HepDirect technology, the project team has identified the lead compound series that demonstrated potent glucose-lowering activity in animal models without causing hypoglycemia mediated mainly through pancreas activity.
Enterocyte-Directed DGAT-1 Inhibitor Program for Obesity or T2DM
DGAT-1 is a key enzyme catalyzing the formation of triglycerides, a main form of fat and is highly expressed in human fat metabolism sites such as intestine, liver, and adipose. Inhibition of the enzyme has shown to reduce fat storage in animal models and clinic, led to reduction of body weight. However, non-selective systemic reduction of fat formation can lead to undesirable side effects demonstrated in DGAT-1 null mice. By introducing a unique chemical function group into the DGAT-1 inhibitors, the project team has developed a series of lead compounds that selectively inhibited DGAT-1 at enterocytes, the intestinal absorptive cells responsible for the absorption of dietary fat, and that demonstrated efficacy in animal models of dietary induced obesity.
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