6bn6

Publication Abstract from PubMed

We disclose the optimization of a high throughput screening hit to yield benzothiazine and tetrahydroquinoline sulfonamides as potent RORgammat inverse agonists. However, a majority of these compounds showed potent activity against pregnane X receptor (PXR) and modest activity against liver X receptor alpha (LXRalpha). Structure-based drug design (SBDD) led to the identification of benzothiazine and tetrahydroquinoline sulfonamide analogs which completely dialed out LXRalpha activity and were less potent at PXR. Pharmacodynamic (PD) data for compound 35 in an IL-23 induced IL-17 mouse model is discussed along with the implications of a high Ymax in the PXR assay for long term preclinical pharmacokinetic (PK) studies.

Identification of bicyclic hexafluoroisopropyl alcohol sulfonamides as retinoic acid receptor-related orphan receptor gamma (RORgamma/RORc) inverse agonists. Employing structure-based drug design to improve pregnane X receptor (PXR) selectivity.,Gong H, Weinstein DS, Lu Z, Duan JJ, Stachura S, Haque L, Karmakar A, Hemagiri H, Raut DK, Gupta AK, Khan J, Camac D, Sack JS, Pudzianowski A, Wu DR, Yarde M, Shen DR, Borowski V, Xie JH, Sun H, D'Arienzo C, Dabros M, Galella MA, Wang F, Weigelt CA, Zhao Q, Foster W, Somerville JE, Salter-Cid LM, Barrish JC, Carter PH, Dhar TGM Bioorg Med Chem Lett. 2018 Jan 15;28(2):85-93. doi: 10.1016/j.bmcl.2017.12.006., Epub 2017 Dec 5. PMID:29233651^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.