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

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

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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