Discovery of <i>N</i>‑(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
10.1021/acsmedchemlett.9b00431.s001
https://acs.figshare.com/articles/journal_contribution/Discovery_of_i_N_i_Indazol-3-yl_piperidine-4-carboxylic_Acids_as_ROR_t_Allosteric_Inhibitors_for_Autoimmune_Diseases/11607417
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 <b>1</b>, a tool compound <b>14</b> 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 <b>14</b> to 4-F-indazole, and incorporating
a key hydroxyl group led to the discovery of <b>25</b>, which
possesses exquisite potency and selectivity, as well as an improved
pharmacokinetic profile suitable for oral dosing.
2020-01-14 20:04:24
Substantial interest
Th 17 cells
benzoic acid moiety
anti-IL -17
selectivity
pharmacokinetic profile
4- aza-indazole core
Th 17 pathway modulation
optimization
ROR γt inhibition
GM-CSF
piperidinyl carboxylate
hormone receptor ROR γt
allosteric binding pocket
off-target profile
hydroxyl group
Autoimmune Diseases
tool compound 14
orthosteric binders
ROR γt Allosteric Inhibitors
master regulator
4- F-indazole
ROR γt inhibitors
potency
-17A
-17F