Indoleamine-2,3-dioxygenase
1 (IDO1) inhibition and its combination
with immune checkpoint inhibitors like pembrolizumab have drawn considerable attention from both academia and the pharmaceutical
industry. Here, we describe the discovery of a novel class of highly
potent IDO1 heme-displacing inhibitors featuring a unique bicyclo[1.1.1]pentane
motif. Compound 1, evolving from an ALIS (automated ligand
identification system) hit, exhibited excellent potency but lacked
the desired pharmacokinetic profile due to extensive amide hydrolysis
of the benzamide moiety. Replacing the central phenyl ring in 1 with a bicyclo[1.1.1]pentane bioisostere effectively circumvented
the amide hydrolysis issue, resulting in the discovery of compound 2 with a favorable overall profile such as excellent potency,
selectivity, pharmacokinetics, and a low predicted human dose.
Checkpoint
inhibitors have demonstrated unprecedented efficacy
and are evolving to become standard of care for certain types of cancers.
However, low overall response rates often hamper the broad utility
and potential of these breakthrough therapies. Combination therapy
strategies are currently under intensive investigation in the clinic,
including the combination of PD-1/PD-L1 agents with IDO1 inhibitors.
Here, we report the discovery of a class of IDO1 heme-binding inhibitors
featuring a unique amino-cyclobutarene motif, which was discovered
through SBDD from a known and weakly active inhibitor. Subsequent
optimization efforts focused on improving metabolic stability and
were greatly accelerated by utilizing a robust SNAr reaction
of a facile nitro-furazan intermediate to quickly explore different
polar side chains. As a culmination of these efforts, compound 16 was identified and demonstrated a favorable overall profile
with superior potency and selectivity. Extensive studies confirmed
the chemical stability and drug-like properties of compound 16, rendering it a potential drug candidate.
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.
Indoleamine-2,3-dioxygenase-1 (IDO1)
has emerged as an attractive
target for cancer immunotherapy. An automated ligand identification
system screen afforded the tetrahydroquinoline class of novel IDO1
inhibitors. Potency and pharmacokinetic (PK) were key issues with
this class of compounds. Structure-based drug design and strategic
incorporation of polarity enabled the rapid improvement on potency,
solubility, and oxidative metabolic stability. Metabolite identification
studies revealed that amide hydrolysis in the D-pocket was the key
clearance mechanism for this class. Strategic survey of amide isosteres
revealed that carbamates and N-pyrimidines, which
maintained exquisite potencies, mitigated the amide hydrolysis issue
and led to an improved rat PK profile. The lead compound 28 is a potent IDO1 inhibitor, with clean off-target profiles and the
potential for quaque die dosing in humans.
Recent data suggest
that the inhibition of arginase (ARG) has therapeutic
potential for the treatment of a number of indications ranging from
pulmonary and vascular disease to cancer. Thus, high demand exists
for selective small molecule ARG inhibitors with favorable druglike
properties and good oral bioavailability. In light of the significant
challenges associated with the unique physicochemical properties of
previously disclosed ARG inhibitors, we use structure-based drug design
combined with a focused optimization strategy to discover a class
of boronic acids featuring a privileged proline scaffold with superior
potency and oral bioavailability. These compounds, exemplified by
inhibitors
4a
,
18
, and
27
,
demonstrated a favorable overall profile, and
4a
was
well tolerated following multiple days of dosing at concentrations
that exceed those required for serum arginase inhibition and concomitant
arginine elevation in a syngeneic mouse carcinoma model.
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