Uncoupling Neuroprotection from Immunosuppression: the Discovery of ILS-920 - Accounts in Drug Discovery Case Studies in Medicinal Chemistry - page 324

Figure 14.5 General trends observed in activity of library rapamycin analogs
screened for neurite outgrowth inducing activity.
novel dienophiles. The initial goal of the program was to improve the potency
of the WAY-124466 scaffold, and in this way identify a lead compound with
acceptable brain penetration and pharamacokinetics for in vivo proof-of-con-
cept. Since the C19,C22 diene cannot easily access the Diels-Alder transition
state, presumably for reasons of geometry and electronics, only very reactive
dienophiles were observed to yield [4 þ 2] cycloadducts at this position. Figure
14.6 summarizes the preliminary structure-activity work that was done, with
reference to various substituted dienophiles.
WYE-592 was synthesized via [4 þ 2] cycloaddition of rapamycin with
nitrosobenzene. WYE-592 exhibited both good brain penetration (brain/whole
blood ¼ 0.52) and increased potency in promoting neurite outgrowth and
neuronal survival compared to both rapamycin and WAY-124466, but the
compound inhibited IL-2-stimulated T-cell proliferation with an IC 50 of
150 nM. This activity is consistent with the 3-5% conversion of WYE-592 to
rapamycin starting material via a retro-Diels-Alder reaction that had been
observed in physiological buffer. This hypothesis is further supported by the
observation that WYE-592 does not bind in vitro to the FRB domain of mTOR
in the presence of FKBP12 (as expected due to the modification of triene),
whereas rapamycin itself exerts its immunosuppressive activity via formation of
an inhibitory complex with FKBP12 and mTOR.
In order to prevent this back-conversion to rapamycin from occurring, the
C20,C21 alkene in WYE-592 was reduced by catalytic hydrogenation over a
Pd/C catalyst to yield ILS-920. In contrast to WYE-592, this compound did not
inhibit T-cell proliferation up to 5 mM. ILS-920 was at least five times more
potent than WYE-592, rapamycin, or GPI-1046 at promoting cortical neuronal
survival (and therefore an order of magnitude more potent than rapamycin),
but yet maintained good brain penetration and acceptable ADME properties.