4 research outputs found
Optimizing a Weakly Binding Fragment into a Potent RORĪ³t Inverse Agonist with Efficacy in an in Vivo Inflammation Model
The
transcription factor RORĪ³t is an attractive drug-target due
to its role in the differentiation of IL-17 producing Th17 cells that
play a critical role in the etiopathology of several autoimmune diseases.
Identification of starting points for RORĪ³t inverse agonists
with good properties has been a challenge. We report the identification
of a fragment hit and its conversion into a potent inverse agonist
through fragment optimization, growing and merging efforts. Further
analysis of the binding mode revealed that inverse agonism was achieved
by an unusual mechanism. In contrast to other reported inverse agonists,
there is no direct interaction or displacement of helix 12 observed
in the crystal structure. Nevertheless, compound <b>9</b> proved
to be efficacious in a delayed-type hypersensitivity (DTH) inflammation
model in rats
Optimizing a Weakly Binding Fragment into a Potent RORĪ³t Inverse Agonist with Efficacy in an in Vivo Inflammation Model
Optimizing a Weakly Binding Fragment into a Potent RORĪ³t Inverse Agonist with Efficacy in an in Vivo Inflammation Model
The
transcription factor RORĪ³t is an attractive drug-target due
to its role in the differentiation of IL-17 producing Th17 cells that
play a critical role in the etiopathology of several autoimmune diseases.
Identification of starting points for RORĪ³t inverse agonists
with good properties has been a challenge. We report the identification
of a fragment hit and its conversion into a potent inverse agonist
through fragment optimization, growing and merging efforts. Further
analysis of the binding mode revealed that inverse agonism was achieved
by an unusual mechanism. In contrast to other reported inverse agonists,
there is no direct interaction or displacement of helix 12 observed
in the crystal structure. Nevertheless, compound <b>9</b> proved
to be efficacious in a delayed-type hypersensitivity (DTH) inflammation
model in rats