Open AccessDiscovery of N-(Indazol-3-yl)piperidine-4-carboxylic Acids as RORγt Allosteric Inhibitors for Autoimmune Diseases
Author(s) -
Hongjun Zhang,
Blair T. Lapointe,
Neville J. Anthony,
Rita Azevedo,
Jos Cals,
Craig C. Correll,
Marc Daniels,
Sujal V. Deshmukh,
Hans van Eenenaam,
Heidi M. Ferguson,
Laxminarayan G. Hegde,
Willem Jan Karstens,
John Maclean,
J. Richard Miller,
Lily Y. Moy,
Vladimir Simov,
Sunil Nagpal,
Arthur Oubrie,
R.L. Palte,
Gopal Parthasarathy,
Nunzio Sciammetta,
Mario van der Stelt,
Janice D Woodhouse,
B. Wesley Trotter,
Kenneth Barr
Publication year - 2020
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.9b00431
Subject(s) - rar related orphan receptor gamma , allosteric regulation , chemistry , indazole , drug discovery , piperidine , potency , pharmacology , stereochemistry , allosteric modulator , receptor , combinatorial chemistry , medicine , biochemistry , in vitro , transcription factor , gene
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.