Inhibition of glucosylceramide
synthase (GCS) is a major therapeutic
strategy for Gaucher’s disease and has been suggested as a
potential target for treating Parkinson’s disease. Herein,
we report the discovery of novel brain-penetrant GCS inhibitors. Assessment
of the structure–activity relationship revealed a unique pharmacophore
in this series. The lipophilic ortho-substituent of aromatic ring
A and the appropriate directionality of aromatic ring B were key for
potency. Optimization of the absorption, distribution, metabolism,
elimination, toxicity (ADMETox) profile resulted in the discovery
of T-036, a potent GCS inhibitor in vivo. Pharmacophore-based
scaffold hopping was performed to mitigate safety concerns associated
with T-036. The ring opening of T-036 resulted
in another potent GCS inhibitor with a lower toxicological risk, T-690, which reduced glucosylceramide in a dose-dependent
manner in the plasma and cortex of mice. Finally, we discuss the structural
aspects of the compounds that impart a unique inhibition mode and
lower the cardiovascular risk.
Aiming to discover melanin-concentrating hormone receptor 1 (MCHR1) antagonists with improved safety profiles, we hypothesized that the aliphatic amine employed in most antagonists reported to date could be removed if the bicyclic motif of the compound scaffold interacted with Asp123 and/or Tyr272 of MCHR1. We excluded aliphatic amines from our compound designs, with a cutoff value of pK(a) < 8, and explored aliphatic amine-free MCHR1 antagonists in a CNS-oriented chemical space limited by four descriptors (TPSA, ClogP, MW, and HBD count). Screening of novel bicyclic motifs with high intrinsic binding affinity for MCHR1 identified the imidazo[1,2-a]pyridine ring (represented in compounds 6a and 6b), and subsequent cyclization of the central aliphatic amide linkage led to the discovery of a potent, orally bioavailable MCHR1 antagonist 4-[(4-chlorobenzyl)oxy]-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one 10a. It exhibited low potential for hERG inhibition and phospholipidosis induction as well as sufficient brain concentration to exert antiobesity effects in diet-induced obese rats.
To discover a novel
series of potent inhibitors of enteropeptidase,
a membrane-bound serine protease localized to the duodenal brush border,
4-guanidinobenzoate derivatives were evaluated with minimal systemic
exposure. The
1c
docking model enabled the installation
of an additional carboxylic acid moiety to obtain an extra interaction
with enteropeptidase, yielding
2a
. The oral administration
of
2a
significantly elevated the fecal protein output,
a pharmacodynamic marker, in diet-induced obese (DIO) mice, whereas
subcutaneous administration did not change this parameter. Thus, systemic
exposure of
2a
was not required for its pharmacological
effects. Further optimization focusing on the in vitro IC
50
value and
T
1/2
, an indicator of dissociation
time, followed by enhanced in vivo pharmacological activity based
on the ester stability of the compounds, revealed two series of potent
enteropeptidase inhibitors, a dihydrobenzofuran analogue (
(
S
)-5b
, SCO-792) and phenylisoxazoline (
6b
), which exhibited potent anti-obesity effects despite their low
systemic exposure following their oral administration to DIO rats.
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