title: RORγt inhibitors as potential back-ups for the phase II candidate VTP-43742 from Vitae Pharmaceuticals: patent evaluation of WO2016061160 and US20160122345.
abstract: Retinoic acid receptor-related orphan nuclear receptor gamma t (RORγt or RORc2) is a key transcription factor for the differentiation of naïve proinflammatory CD4+T cells and the production of T helper-17 (TH17) cells. Inhibiting RORγt activity is thought to be beneficial in targeting a variety of inflammatory and autoimmune disorders. Recently Vitae Pharmaceuticals (to be acquired by Allergan) reported positive top-line results from a Phase 2a clinical trial of RORγt inhibitor VTP-43742 in psoriatic patients. The compound was reported to demonstrate a clear signal of efficacy over a short four-week period and no drug-related cardiac abnormalities were observed; however, in the 700 mg dose group reversible transaminase elevations were observed in four patients, which prompted the company to cancel testing VTP-43742 at a initially planned third, higher dose. In Vitae Pharmaceuticals latest patent applications, WO2016061160 and US20160122345, potential dihydropyrrolopyridine back-up compounds of clinical candidate VTP-43742 (covered in WO2015116904) are disclosed. In light of the recently announced RORγt back-up molecule VTP-45489, the improvements of the new compounds are discussed and their potential impact is elucidated.
authors.affiliation: a Phenex Pharmaceuticals AG , Waldhofer Straße 104, 69123 Heidelberg , Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Gege
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000037:antagonists & inhibitors*; D010330:Patents as Topic; D011565:Psoriasis / Q000188:drug therapy; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D011759:Pyrrolidines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D016896:Treatment Outcome
chemical_list: D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D011725:Pyridines; D011759:Pyrrolidines; C000615700:VTP-43742
keywords: RORc2; RORγt; Retinoid-related orphan receptor gamma t; VTP-43742; VTP-45489; back-up compound