Uncoupling Neuroprotection from Immunosuppression: the Discovery of ILS-920 - Accounts in Drug Discovery Case Studies in Medicinal Chemistry - page 327

ILS-920 was selected as a suitable candidate for in vivo testing based upon its
lack of immunosuppression, superior potency, and pharmacokinetic properties
in addition to its improved stability relative to WYE-592. A rodent model of
surgically-induced ischemic stroke was chosen for initial evaluation, with
subsequent follow up in non-human primates, with a particular focus on
extending the treatment window. Treatment with ILS-920 at 10 and 30mg
kg 1 , administered intravenously (iv) 4 h post-occlusion, significantly reduced
infarct volume and improved neurological recovery in a transient mid-cerebral
artery occlusion (tMCAO) rat model of ischemic stroke. Additionally, rats were
given iv doses of 10 or 30mg kg 1 of ILS-920 at 24 h post-induction of per-
manent MCAO, with four additional doses administered once daily, and
neurological deficits assessed over 21 days post-stroke. The data show that rats
treated with 30mg kg 1 ILS-920 displayed a significantly improved slope of
recovery and significantly improved neurological scores at 21 days post-MCAO
relative to vehicle treated animals. 55
The in vivo ecacy of ILS-920 is in marked contrast to rapamycin, which
failed to reduce infarct volume in a rat tMCAO model. 49 GPI-1046 was also
reported to have limited or no ecacy in comparable models of ischemic
stroke. 51 N-(N 0 ,N 0 -Dimethylcarboxamidomethyl)cycloheximide (DM-CHX)
was reported to reduce infarct volume by up to 44% when delivered via
intracerebroventricular (icv) application 2 h post-occlusion (but not 6 h) in a rat
model of endothelin-induced transient focal ischemia. 24 Since icv application is
impractical for human stroke patients, in the absence of data employing
alternate routes of delivery it is unclear at present what the clinical utility of
such a compound might be. In contrast, treatment with ILS-920 results in
significant enhancement of neurological recovery in a tMCAO model of stroke
with at least a 24 h therapeutic window (time elapsed between insult and initial
dose) when delivered intravenously. Clinical evaluation of ILS-920 was initi-
ated in 2009. 56
14.5 Concluding Remarks
Current paradigms of drug discovery present an interesting, if vexing, con-
undrum. It is universally acknowledged that therapeutic indications having
high unmet medical need represent the best areas to invest resources and effort
in terms of both the potential impact to health and untapped market potential.
However, these same areas of focus are also expected to demand innovative
approaches outside those tried before (approaches that would presumably have
yielded solutions long ago), which adds a considerable amount of risk to an
already long, dicult, expensive, and attrition-prone R&D process. Ironically,
an older paradigm from an earlier era of drug discovery, namely natural pro-
duct research, represents a potential bridge to balancing risk and innovation
that complements modern synthetic chemistry approaches. On the one hand,
these privileged structures (that have withstood the selective pressures of eons
of natural selection) have already proven their utility in human medicine.