Defining Target Engagement Required for Efficacy In Vivo at the Retinoic Acid Receptor-Related Orphan Receptor C2 (RORγt).

Autor:	Lugar CW; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States., Clarke CA; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States., Morphy R; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States., Rudyk H; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States., Sapmaz S; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States., Stites RE; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States., Vaught GM; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States., Furness K; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States., Broughton HB; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States., Durst GL; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States., Clawson DK; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States., Stout SL; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States., Guo SY; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States., Durbin JD; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States., Stayrook KR; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States., Edmondson DD; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States., Kikly K; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States., New NE; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States., Bina HA; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States., Chambers MG; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States., Shetler P; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States., Chang WY; Lilly Biotechnology Center, Eli Lilly and Company, San Diego, California 92121, United States., Chang VC; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States., Barr R; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States., Gough WH; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States., Steele JP; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States., Getman B; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States., Patel N; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States., Mathes BM; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States., Richardson TI; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2021 May 13; Vol. 64 (9), pp. 5470-5484. Date of Electronic Publication: 2021 Apr 14.
DOI:	10.1021/acs.jmedchem.0c01918
Abstrakt:	The Th17 pathway has been implicated in autoimmune diseases. The retinoic acid receptor-related orphan receptor C2 (RORγt) is a master regulator of Th17 cells and controls the expression of IL-17A. RORγt is expressed primarily in IL-17A-producing lymphoid cells. Here we describe a virtual screen of the ligand-binding pocket and subsequent screen in a binding assay that identified the 1-benzyl-4',5'-dihydrospiro[piperidine-4,7'-thieno[2,3- c ]pyran]-2'-carboxamide scaffold as a starting point for optimization of binding affinity and functional activity guided by structure-based design. Compound 12 demonstrated activity in a mouse PK/PD model and efficacy in an inflammatory arthritis mouse model that were used to define the level and duration of target engagement required for efficacy in vivo . Further optimization to improve ADME and physicochemical properties with guidance from simulations and modeling provided compound 22 , which is projected to achieve the level and duration of target engagement required for efficacy in the clinic.
Databáze:	MEDLINE
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