We report the discovery
of a novel indoleamine 2,3-dioxygenase-1
(IDO1) inhibitor class through the affinity selection of a previously
unreported indole-based DNA-encoded library (DEL). The DEL exemplar,
spiro-chromane 1, had moderate IDO1 potency but high
in vivo clearance. Series optimization quickly afforded a potent,
low in vivo clearance lead 11. Although amorphous 11 was highly bio-available, crystalline 11 was
poorly soluble and suffered disappointingly low bio-availability because
of solubility-limited absorption. A prodrug approach was deployed
and proved effective in discovering the highly bio-available phosphonooxymethyl 31, which rapidly converted to 11 in vivo. Obtaining
crystalline 31 proved problematic, however; thus salt
screening was performed in an attempt to circumvent this obstacle
and successfully delivered greatly soluble and bio-available crystalline
tris-salt 32. IDO1 inhibitor 32 is characterized
by a low calculated human dose, best-in-class potential, and an unusual
inhibition mode by binding the IDO1 heme-free (apo) form.
We previously described the discovery
of GSK5852 (1), a non-nucleoside polymerase (NS5B) inhibitor
of hepatitis C virus (HCV), in which an N-benzyl
boronic acid was essential for potent antiviral activity. Unfortunately,
facile benzylic oxidation resulted in a short plasma half-life (5
h) in human volunteers, and a backup program was initiated to remove
metabolic liabilities associated with 1. Herein, we describe
second-generation NS5B inhibitors including GSK8175 (49), a sulfonamide-N-benzoxaborole analog with low
in vivo clearance across preclinical species and broad-spectrum activity
against HCV replicons. An X-ray structure of NS5B protein cocrystallized
with 49 revealed unique protein-inhibitor interactions
mediated by an extensive network of ordered water molecules and the
first evidence of boronate complex formation within the binding pocket.
In clinical studies, 49 displayed a 60–63 h half-life
and a robust decrease in viral RNA levels in HCV-infected patients,
thereby validating our hypothesis that reducing benzylic oxidation
would improve human pharmacokinetics and lower efficacious doses relative
to 1.
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