Literature DB >> 25017032

Reduction in lipophilicity improved the solubility, plasma-protein binding, and permeability of tertiary sulfonamide RORc inverse agonists.

Benjamin P Fauber1, Olivier René2, Gladys de Leon Boenig2, Brenda Burton3, Yuzhong Deng2, Céline Eidenschenk2, Christine Everett2, Alberto Gobbi2, Sarah G Hymowitz2, Adam R Johnson2, Hank La2, Marya Liimatta2, Peter Lockey3, Maxine Norman3, Wenjun Ouyang2, Weiru Wang2, Harvey Wong2.   

Abstract

Using structure-based drug design principles, we identified opportunities to reduce the lipophilicity of our tertiary sulfonamide RORc inverse agonists. The new analogs possessed improved RORc cellular potencies with >77-fold selectivity for RORc over other nuclear receptors in our cell assay suite. The reduction in lipophilicity also led to an increased plasma-protein unbound fraction and improvements in cellular permeability and aqueous solubility.
Copyright © 2014 Elsevier Ltd. All rights reserved.

Entities:  

Keywords:  IL-17; Permeability; RORc; RORγ; Solubility; X-ray structure

Mesh：

Substances：

Year:  2014        PMID： 25017032     DOI： 10.1016/j.bmcl.2014.06.048

Source DB:  PubMed          Journal:  Bioorg Med Chem Lett        ISSN： 0960-894X            Impact factor:   2.823


  13 in total

1.  SAR Exploration Guided by LE and Fsp(3): Discovery of a Selective and Orally Efficacious RORγ Inhibitor.

Authors:  Kazuyuki Hirata; Masayuki Kotoku; Noriyoshi Seki; Takaki Maeba; Katsuya Maeda; Shintaro Hirashima; Takayuki Sakai; Shingo Obika; Akimi Hori; Yasunori Hase; Takayuki Yamaguchi; Yoshiaki Katsuda; Takahiro Hata; Naoki Miyagawa; Kojo Arita; Yukihiro Nomura; Kota Asahina; Yusuke Aratsu; Masafumi Kamada; Tsuyoshi Adachi; Masato Noguchi; Satoki Doi; Paul Crowe; Erin Bradley; Ruo Steensma; Haiyan Tao; Morgan Fenn; Robert Babine; Xiaolin Li; Scott Thacher; Hiromasa Hashimoto; Makoto Shiozaki
Journal:  ACS Med Chem Lett       Date:  2015-11-04       Impact factor: 4.345

2.  Minor Structural Change to Tertiary Sulfonamide RORc Ligands Led to Opposite Mechanisms of Action.

Authors:  Olivier René; Benjamin P Fauber; Gladys de Leon Boenig; Brenda Burton; Céline Eidenschenk; Christine Everett; Alberto Gobbi; Sarah G Hymowitz; Adam R Johnson; James R Kiefer; Marya Liimatta; Peter Lockey; Maxine Norman; Wenjun Ouyang; Heidi A Wallweber; Harvey Wong
Journal:  ACS Med Chem Lett       Date:  2014-12-04       Impact factor: 4.345

Review 3.  ROR nuclear receptors: structures, related diseases, and drug discovery.

Authors:  Yan Zhang; Xiao-yu Luo; Dong-hai Wu; Yong Xu
Journal:  Acta Pharmacol Sin       Date:  2014-12-15       Impact factor: 6.150

4.  Discovery of Biaryl Amides as Potent, Orally Bioavailable, and CNS Penetrant RORγt Inhibitors.

Authors:  Yonghui Wang; Wei Cai; Yaobang Cheng; Ting Yang; Qian Liu; Guifeng Zhang; Qinghua Meng; Fangbin Han; Yafei Huang; Ling Zhou; Zhijun Xiang; Yong-Gang Zhao; Yan Xu; Ziqiang Cheng; Sijie Lu; Qianqian Wu; Jia-Ning Xiang; John D Elliott; Stewart Leung; Feng Ren; Xichen Lin
Journal:  ACS Med Chem Lett       Date:  2015-05-26       Impact factor: 4.345

5.  Statistical Analysis of Protein-Ligand Interaction Patterns in Nuclear Receptor RORγ.

Authors:  Bill Pham; Ziju Cheng; Daniel Lopez; Richard J Lindsay; David Foutch; Rily T Majors; Tongye Shen
Journal:  Front Mol Biosci       Date:  2022-06-15

6.  Identification of potent RORβ modulators: Scaffold variation.

Authors:  Christelle Doebelin; Rémi Patouret; Ruben D Garcia-Ordonez; Mi Ra Chang; Venkatasubramanian Dharmarajan; Scott Novick; Anthony Ciesla; Sean Campbell; Laura A Solt; Patrick R Griffin; Theodore M Kamenecka
Journal:  Bioorg Med Chem Lett       Date:  2018-08-16       Impact factor: 2.823

7.  A New Highly Reactive and Low Lipophilicity Fluorine-18 Labeled Tetrazine Derivative for Pretargeted PET Imaging.

Authors:  Outi Keinänen; Xiang-Guo Li; Naveen K Chenna; Dave Lumen; Jennifer Ott; Carla F M Molthoff; Mirkka Sarparanta; Kerttuli Helariutta; Tapani Vuorinen; Albert D Windhorst; Anu J Airaksinen
Journal:  ACS Med Chem Lett       Date:  2015-12-10       Impact factor: 4.345

8.  Discovery and structural optimization of 4-(4-(benzyloxy)phenyl)-3,4-dihydropyrimidin-2(1H)-ones as RORc inverse agonists.

Authors:  Xi-Shan Wu; Rui Wang; Yan-Li Xing; Xiao-Qian Xue; Yan Zhang; Yong-Zhi Lu; Yu Song; Xiao-Yu Luo; Chun Wu; Yu-Lai Zhou; Jian-Qin Jiang; Yong Xu
Journal:  Acta Pharmacol Sin       Date:  2016-07-04       Impact factor: 6.150

9.  Discovery of Retinoic Acid-Related Orphan Receptor γt Inverse Agonists via Docking and Negative Image-Based Screening.

Authors:  Sanna Rauhamäki; Pekka A Postila; Sakari Lätti; Sanna Niinivehmas; Elina Multamäki; Klaus R Liedl; Olli T Pentikäinen
Journal:  ACS Omega       Date:  2018-06-11

10.  Identification of an allosteric binding site for RORγt inhibition.

Authors:  Marcel Scheepstra; Seppe Leysen; Geert C van Almen; J Richard Miller; Jennifer Piesvaux; Victoria Kutilek; Hans van Eenennaam; Hongjun Zhang; Kenneth Barr; Sunil Nagpal; Stephen M Soisson; Maria Kornienko; Kristen Wiley; Nathaniel Elsen; Sujata Sharma; Craig C Correll; B Wesley Trotter; Mario van der Stelt; Arthur Oubrie; Christian Ottmann; Gopal Parthasarathy; Luc Brunsveld
Journal:  Nat Commun       Date:  2015-12-07       Impact factor: 14.919
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