10.1002/cmdc.202000385
ChemMedChem
COMMUNICATION
used in clinical trials, generally with healthy, young male
subjects.[18] mAChR blockade does not hinder the ability to learn,
but causes reversible amnesia. Both E-64d (a non-selective
calpain-1 inhibitor) and 1c were shown to restore memory in mice
in step-through passive avoidance (STPA), a hippocampus-
dependent learning and memory task.[19] Before training using an
electric shock in the dark compartment, the mice were
administered scopolamine (1 mg/kg) followed by either 1c (10
mg/kg), E-64d (10 mg/kg), or vehicle control. Mice administered
vehicle did not remember to avoid the dark compartment, with
significantly lower latency to enter the dark compartment than the
untreated controls (57.1 ± 20.1 versus 256.4 ± 20.4 sec; Figure
3). For mice that were treated with either 1c or E-64d the latency
to enter the dark compartment increased significantly (193.1 ±
42.8 and 187.1 ± 27.4 sec, respectively).
Acknowledgements
The King Abdullah Science scholarship to A.J. and the
T32AG057468 grant to R.K.
Keywords: calpain 1 • chirality 2 • cysteine proteases 3 • α-
ketoamides 4 • peptidomimetics 5
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In summary, a set of stereochemically pure α-ketoamides
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synthetic route. We showed that all the analogs with the (S)-
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calpain-1. Modeling studies using an X-ray crystal structure of
calpain-1 with the known α-ketoamide-based inhibitor, SNJ-1945,
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that of the original ligand. Additionally, the predicted weaker
binding affinity for the (R,R)-diastereomer 1g that can be
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greatly reduced potency. It should be noted that ABT-957 is a
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interruption of REM-sleep as
endpoint for ABT-957 was based upon preclinical animal studies
in which sleep perturbations were observed for ABT-957 and were
a clinical pharmacodynamic
proposed to be
a functional consequence of increased
extracellular acetylcholine (ACh).[20] In 17 healthy men aged 25-
45 years with regular sleep habits, ABT-957 failed to achieve this
primary endpoint.[11] However, this pharmacodynamic readout
does not directly test the calpain-cathepsin hypothesis, nor
calpain-1 engagement.
Measured CSF concentrations of ABT-957 (9-21 nM) did not
reach the IC50 for calpain inhibition in biochemical assays, even
at the highest doses. However, plasma concentrations were much
higher than IC50 and across five Phase 1 study arms, including
aged subjects, no treatment-associated adverse events were
identified, representing a very strong safety signal.
The results of this Phase 1 study do not resolve the question
of selective calpain versus dual calpain/cathepsin inhibition as a
therapeutic approach to neurodegeneration, neurotrauma, and
other CNS disorders. The protection of neurons and indeed the
neurovascular unit by calpain inhibitors also remains to be tested
in human subjects.
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Experimental procedures are available in the Supporting Information
5
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