Uncoupling Neuroprotection from Immunosuppression: the Discovery of ILS-920 - Accounts in Drug Discovery Case Studies in Medicinal Chemistry - page 322

Figure 14.4 The structure of GPI-1046 showing its origin from the immunophilin
binding domain of FK-506.
domains may be more potent neuroprotective agents, and may also be less
immunosuppressive.
In the course of screening our library of microbial fermentation extracts for
compounds that bind to immunophilins, we identified a culture (subsequently
identified as Streptomyces sp. LL-C31037) that produced a previously unre-
ported compound, 3-normeridamycin (Figure 14.1). This new natural product
exhibited potent restoration of dopamine uptake in 1-methyl-4-phenylpyr-
idinium (MPP 1 ) challenged neurons, with statistical significance down to low
nanomolar concentrations. The biological activity of 3-normeridamycin stands
in marked contrast to FK-506 and rapamycin (Table 14.1). The apparent
lack of any correlation between neuroprotection and binding to FKBP12 is
consistent with previous reports. The discovery of the neuroprotective activity
of 3-normeridamycin supported our hypothesis that non-calcineurin/mTOR
effector domains may be relevant for neuroprotection, and furthermore
suggested that as-yet unreported protein partners may bind to the natural
product-immunophilin complex.
Encouraged by the results of screening for immunophilin binders, we then
reexamined a representative set of compounds developed in the course of earlier
medicinal chemistry programs based on the rapamycin scaffold. Approximately
70 compounds were selected on the basis of structural diversity, purity/integ-
rity, and availability. These compounds were tested for promotion of neuronal
survival using a neurofilament (NF) ELISA assay (CTX) and neurite out-
growth (NRO) activity in cortical neurons using a Cellomics Arrayscan assay
platform. 52 We found that the non-immunosuppressive rapamycin analog
(rapalog) WAY-124466 (1) had activity (EC 50 ¼ 0.8 mM) in promoting survival
of cortical neurons in culture. 47 The initial observations from this analysis of
library rapalogs are summarized in Figure 14.5.
Therefore, a medicinal chemistry effort was initiated to identify a series of
rapalogs modified at the C19,C22 diene employing Diels-Alder chemistry with