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

Hongjun Zhang; Blair T Lapointe; Neville Anthony; Rita Azevedo; Jos Cals; Craig C Correll; Matthew Daniels; Sujal Deshmukh; Hans van Eenenaam; Heidi Ferguson; Laxminarayan G Hegde; Willem Jan Karstens; John Maclean; J Richard Miller; Lily Y Moy; Vladimir Simov; Sunil Nagpal; Arthur Oubrie; Rachel L Palte; Gopal Parthasarathy; Nunzio Sciammetta; Mario van der Stelt; Janice D Woodhouse; B Wesley Trotter; Kenneth Barr

doi:10.1021/acsmedchemlett.9b00431

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. eCollection 2020 Feb 13.

Authors

Hongjun Zhang¹, Blair T Lapointe¹, Neville Anthony¹, Rita Azevedo², Jos Cals², Craig C Correll¹, Matthew Daniels¹, Sujal Deshmukh¹, Hans van Eenenaam², Heidi Ferguson¹, Laxminarayan G Hegde¹, Willem Jan Karstens², John Maclean¹, J Richard Miller¹, Lily Y Moy¹, Vladimir Simov¹, Sunil Nagpal¹, Arthur Oubrie², Rachel L Palte¹, Gopal Parthasarathy³, Nunzio Sciammetta¹, Mario van der Stelt², Janice D Woodhouse¹, B Wesley Trotter¹, Kenneth Barr¹

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.

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.