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Azatricyclic Inverse Agonists of RORγt That Demonstrate Efficacy in Models of Rheumatoid Arthritis and Psoriasis.

ABSTRACT: Structure-activity relationship studies directed toward the replacement of the fused phenyl ring of the lead hexahydrobenzoindole RORγt inverse agonist series represented by 1 with heterocyclic moieties led to the identification of three novel aza analogs 5-7. The hexahydropyrrolo[3,2-f]quinoline series 5 (X = N, Y = Z=CH) showed potency and metabolic stability comparable to series 1 but with improved in vitro membrane permeability and serum free fraction. This structural modification was applied to the hexahydrocyclopentanaphthalene series 3, culminating in the discovery of 8e as a potent and selective RORγt inverse agonist with an excellent in vitro profile, good pharmacokinetic properties, and biologic-like in vivo efficacy in preclinical models of rheumatoid arthritis and psoriasis.

SUBMITTER: Liu Q 

PROVIDER: S-EPMC8155243 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Azatricyclic Inverse Agonists of RORγt That Demonstrate Efficacy in Models of Rheumatoid Arthritis and Psoriasis.

Liu Qingjie Q   Xiao Hai-Yun HY   Batt Douglas G DG   Xiao Zili Z   Zhu Yeheng Y   Yang Michael G MG   Li Ning N   Yip Shiuhang S   Li Peng P   Sun Dawn D   Wu Dauh-Rurng DR   Ruzanov Max M   Sack John S JS   Weigelt Carolyn A CA   Wang Jinhong J   Li Sha S   Shuster David J DJ   Xie Jenny H JH   Song Yunling Y   Sherry Tara T   Obermeier Mary T MT   Fura Aberra A   Stefanski Kevin K   Cornelius Georgia G   Chacko Silvi S   Khandelwal Purnima P   Dudhgaonkar Shailesh S   Rudra Anjuman A   Nagar Jignesh J   Murali Venkata V   Govindarajan Arun A   Denton Rex R   Zhao Qihong Q   Meanwell Nicholas A NA   Borzilleri Robert R   Dhar T G Murali TGM  

ACS medicinal chemistry letters 20210430 5

Structure-activity relationship studies directed toward the replacement of the fused phenyl ring of the lead hexahydrobenzoindole RORγt inverse agonist series represented by <b>1</b> with heterocyclic moieties led to the identification of three novel aza analogs <b>5</b>-<b>7</b>. The hexahydropyrrolo[3,2-<i>f</i>]quinoline series <b>5</b> (X = N, Y = Z=CH) showed potency and metabolic stability comparable to series <b>1</b> but with improved <i>in vitro</i> membrane permeability and serum free  ...[more]

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