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

  • ACS Med Chem Lett. 2020 Jan 9;11(2):114-119. doi: 10.1021/acsmedchemlett.9b00431.
Hongjun Zhang  1 ,  Blair T Lapointe  1 ,  Neville Anthony  1 ,  Rita Azevedo  2 ,  Jos Cals  2 ,  Craig C Correll  1 ,  Matthew Daniels  1 ,  Sujal Deshmukh  1 ,  Hans van Eenenaam  2 ,  Heidi Ferguson  1 ,  Laxminarayan G Hegde  1 ,  Willem Jan Karstens  2 ,  John Maclean  1 ,  J Richard Miller  1 ,  Lily Y Moy  1 ,  Vladimir Simov  1 ,  Sunil Nagpal  1 ,  Arthur Oubrie  2 ,  Rachel L Palte  1 ,  Gopal Parthasarathy  3 ,  Nunzio Sciammetta  1 ,  Mario van der Stelt  2 ,  Janice D Woodhouse  1 ,  B Wesley Trotter  1 ,  Kenneth Barr  1
Affiliations
  • 1. 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.
  • 2. Medicinal Chemistry, Discovery Biology, and Computational and Structural Chemistry, Merck Sharp & Dohme, Molenstraat 110, Oss 5342 CC, The Netherlands.
  • 3. Computational and Structural Chemistry, Merck & Co., Inc., 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States.
PMID: 32071676 DOI: 10.1021/acsmedchemlett.9b00431
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 1, a tool compound 14 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 14 to 4-F-indazole, and incorporating a key hydroxyl group led to the discovery of 25, which possesses exquisite potency and selectivity, as well as an improved pharmacokinetic profile suitable for oral dosing.

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