| Structural highlights
Function
RORG_HUMAN Possible nuclear receptor for hydroxycholesterols, the binding of which strongly promotes coactivators recruitment. Essential for thymopoiesis and the development of several secondary lymphoid tissues, including lymph nodes. Involved in lineage specification of uncommitted CD4(+) T-helper cells into Th17 cells. Regulate the expression of several components of the circadian clock.
Publication Abstract from PubMed
A novel series of RORgamma inhibitors was identified starting with the HTS hit 1. After SAR investigation based on a prospective consideration of two drug-likeness metrics, ligand efficiency (LE) and fraction of sp(3) carbon atoms (Fsp(3)), significant improvement of metabolic stability as well as reduction of CYP inhibition was observed, which finally led to discovery of a selective and orally efficacious RORgamma inhibitor 3z.
SAR Exploration Guided by LE and Fsp(3): Discovery of a Selective and Orally Efficacious RORgamma Inhibitor.,Hirata K, Kotoku M, Seki N, Maeba T, Maeda K, Hirashima S, Sakai T, Obika S, Hori A, Hase Y, Yamaguchi T, Katsuda Y, Hata T, Miyagawa N, Arita K, Nomura Y, Asahina K, Aratsu Y, Kamada M, Adachi T, Noguchi M, Doi S, Crowe P, Bradley E, Steensma R, Tao H, Fenn M, Babine R, Li X, Thacher S, Hashimoto H, Shiozaki M ACS Med Chem Lett. 2015 Nov 4;7(1):23-7. doi: 10.1021/acsmedchemlett.5b00253., eCollection 2016 Jan 14. PMID:26819660[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Hirata K, Kotoku M, Seki N, Maeba T, Maeda K, Hirashima S, Sakai T, Obika S, Hori A, Hase Y, Yamaguchi T, Katsuda Y, Hata T, Miyagawa N, Arita K, Nomura Y, Asahina K, Aratsu Y, Kamada M, Adachi T, Noguchi M, Doi S, Crowe P, Bradley E, Steensma R, Tao H, Fenn M, Babine R, Li X, Thacher S, Hashimoto H, Shiozaki M. SAR Exploration Guided by LE and Fsp(3): Discovery of a Selective and Orally Efficacious RORgamma Inhibitor. ACS Med Chem Lett. 2015 Nov 4;7(1):23-7. doi: 10.1021/acsmedchemlett.5b00253., eCollection 2016 Jan 14. PMID:26819660 doi:http://dx.doi.org/10.1021/acsmedchemlett.5b00253
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