Identification of bicyclic hexafluoroisopropyl alcohol sulfonamides as retinoic acid receptor-related orphan receptor gamma (RORγ/RORc) inverse agonists. Employing structure-based drug design to improve pregnane X receptor (PXR) selectivity.

Authors :: 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
Source :: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2018 Jan 15; Vol. 28 (2), pp. 85-93. Date of Electronic Publication: 2017 Dec 05.
Publication Year :: 2018
Abstract: We disclose the optimization of a high throughput screening hit to yield benzothiazine and tetrahydroquinoline sulfonamides as potent RORγt inverse agonists. However, a majority of these compounds showed potent activity against pregnane X receptor (PXR) and modest activity against liver X receptor α (LXRα). Structure-based drug design (SBDD) led to the identification of benzothiazine and tetrahydroquinoline sulfonamide analogs which completely dialed out LXRα 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 Y <subscript>max</subscript> in the PXR assay for long term preclinical pharmacokinetic (PK) studies.<br /> (Copyright © 2017 Elsevier Ltd. All rights reserved.)

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