Discovery of phenoxyindazoles and phenylthioindazoles as RORγ inverse agonists

RORγ Structural Plasticity and Druggability

“…We compared the binding modes of nine ligands (Figure 7). Compounds 1-8 were co-crystallized with the LBD [11,[37][38][39][40]. Compound 9 was modeled from MD simulations [41].…”

“…Thus, the pocket is extendable depending on the ligand chemistry. (3) 5C4U [11]; (4) 5C4T [11]; (5) 6UCG [37]; (6) 6TLM [38]; (7) 5LWP [39]; (8) 6SAL [40]. No PDB code is available for compound (9) [41].…”

RORγ Structural Plasticity and Druggability

“…We compared the binding modes of nine ligands (Figure 7). Compounds 1 -8 were cocrystallized with the LBD [11,[38][39][40][41]. Compound 9 was modeled from MD simulations [42].…”

“…Allosteric inverse agonists binding in the AF-2 site. The corresponding PDB codes for the co-crystal models of the compounds binding in the RORγ LBD are listed as follows:(1) 4YPQ, 5C4O[11]; (2) 5C4S[11]; (3) 5C4U[11]; (4) 5C4T[11]; (5) 6UCG[38]; (6) 6TLM[39]; (7) 5LWP[40]; (8) 6SAL[41]. No PDB code is available for compound 9[42].…”

Discovery and Characterization of CD12681, a Potent RORγ Inverse Agonist, Preclinical Candidate for the Topical Treatment of Psoriasis

“…Previously published efforts by this group to identify topical RORγ inverse agonists have culminated in the identification of potent phenoxyindazole allosteric inverse agonists . Unfortunately, despite extensive investigation, compounds in this series without predicted phototoxicity were not identified . Phototoxicity was deemed too big a liability for a topical agent and other chemotypes were therefore investigated.…”