Drug Discovery

In its proprietary drug discovery programs, Phenex focuses on the emerging drug targets FXR and LXR.

 

FXR Program in Diabetes and Liver Disorders

FXR (NR1H4, synonyms: BAR = bile acid receptor) is the body´s nuclear bile acid sensor. As a result, it modulates both, the synthetic output of bile acids in the liver and their recycling in the intestine (by regulating bile acid binding proteins). But beyond bile acid physiology, FXR is involved in the regulation of many diverse physiological processes which are relevant in the etiology of and for the treatment of diseases as diverse as metabolic disorders such as Type II Diabetes, dyslipidemias or obesity, chronic inflammatory diseases such as Inflammatory Bowel Diseases or chronic intrahepatic forms of cholestasis.

Phenex currently focuses in its program on the discovery of novel proprietary FXR agonists for the treatment of Type II diabetes. FXR is well suited as a drug target for orally available small molecular Type II Diabetes drugs because:

  1. It binds small molecule ligands (bile acids) naturally.

  2. Activation of FXR increases insulin sensitivity, lowers triglycerides, increases liver glycogen and potentially reduces body weight in relevant animal models (reviewed in Wang et al. Cell Res. 18(11) 1087 (2008), Zhang and Edwards FEBS Lett. 582(1)10 (2008), and Rader DJ Am J Cardiol. 100(11 A):n15 (2007)).

  3. FXR shows no obvious liability compared to other oral insulin sensitizers such as PPARγ (Rosi- and Pioglitazone) or dual PPARα/PPARγ targeted drugs (e.g."Glitazars").

Phenex has filed several patent applications on novel chemical matter and was already granted some patents in the FXR field. From its best performing chemical series, Phenex has nominated Px-101 as its drug candidate for further preclinical and clinical development, a potent and selective FXR agonist with a favorable PK/ADME profile. IND filing is expected for late 2009.

Beyond metabolic diseases, FXR offers several therapeutic opportunities in the treatment of severe liver and gastrointestinal diseases due to its strong hepatoprotective and anticancer functions (reviewed in Zollner and Trauner Br J Pharmacol. 156(1):7-27 (2009), D´Errico and Moschetta Cell Mol Life Sci. 65(10):1523 (2008) and Wang et al. Histol Histopathol. 23(5):621 (2008)) A second FXR series (Px-200), chemically unrelated to Px-101 and with a distinct profile, is currently under evaluation for such non-metabolic medical applications.