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Discovery of -(Indazol-3-yl)piperidine-4-carboxylic Acids as RORγt Allosteric Inhibitors for Autoimmune Diseases. | LitMetric

Discovery of -(Indazol-3-yl)piperidine-4-carboxylic Acids as RORγt Allosteric Inhibitors for Autoimmune Diseases.

ACS Med Chem Lett

Medicinal Chemistry, Discovery Biology, Discovery Process Chemistry, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Discovery Pharmaceutical Sciences, Modeling & Informatics, In Vitro and In Vivo Pharmacology, and Computational and Structural Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.

Published: February 2020

AI Article Synopsis

Article Abstract

The clinical success of anti-IL-17 monoclonal antibodies (i.e., Cosentyx and Taltz) has validated Th17 pathway modulation for the treatment of autoimmune diseases. The nuclear hormone receptor RORγt is a master regulator of Th17 cells and affects the production of a host of cytokines, including IL-17A, IL-17F, IL-22, IL-26, and GM-CSF. Substantial interest has been spurred across both academia and industry to seek small molecules suitable for RORγt inhibition. A variety of RORγt inhibitors have been reported in the past few years, the majority of which are orthosteric binders. Here we disclose the discovery and optimization of a class of inhibitors, which bind differently to an allosteric binding pocket. Starting from a weakly active hit , a tool compound was quickly identified that demonstrated superior potency, selectivity, and off-target profile. Further optimization focused on improving metabolic stability. Replacing the benzoic acid moiety with piperidinyl carboxylate, modifying the 4-aza-indazole core in to 4-F-indazole, and incorporating a key hydroxyl group led to the discovery of , which possesses exquisite potency and selectivity, as well as an improved pharmacokinetic profile suitable for oral dosing.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7025379PMC
http://dx.doi.org/10.1021/acsmedchemlett.9b00431DOI Listing

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