title: Retinoid-related orphan receptor gamma t (RORγt) inhibitors from Vitae Pharmaceuticals (WO2015116904) and structure proposal for their Phase I candidate VTP-43742.
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, however current candidates remain to be validated in the clinic. Recently Vitae Pharmaceuticals successfully finished its Phase 1 single ascending dose clinical study with their proprietary RORγt inverse agonist VTP-43742. On the basis of the reported promising results, Vitae Pharmaceuticals could currently be considered as having the leading clinical candidate in the RORγt inverse agonist category. This prompts the interest on the exact chemical structure of their clinical candidate. The first relevant patent application (WO2014179564) from Vitae Pharmaceuticals describes RORγt inverse agonists with a 5,6-dihydro-4H-pyrrolo[3,4-d]thiazole core, while in the second and latest patent application (WO2015116904) this element has changed towards a 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine core. By combining information from Vitae's patent applications and trustworthy online information, the potential elucidation of the chemical structure of clinical candidate VTP-43742 is described.
authors.affiliation: a Phenex Pharmaceuticals AG , Heidelberg , Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Gege
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000473:pathology; D015195:Drug Design; D054314:Drug Inverse Agonism; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010330:Patents as Topic; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D011725:Pyridines; D011759:Pyrrolidines; C000615700:VTP-43742
keywords: JTE-151; RORC2; RORγt; Retinoid-related orphan receptor gamma t; VTP-43742