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Biotech / Medical : Guilford (GLFD) - Steadily Rising
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To: Miljenko Zuanic who wrote (74)8/25/1997 2:51:00 AM
From: SteveG   of 496
 
<Any idea why GLFD tested GPI-1046 at 3 or 10 mg/kg (PNAS: s.c. injection which IMO can give ~50-250 microM plasma conc.) while it is active at picoM (Ki50 ~50pM) in-vitro. This is ~100K to 1M fold increase compared to in-vitro study.>

You raise an interesting point.

Not having a direct response, I will emphasize, as you already have pointed out, that the 1046 potency of 53pM was *in-vitro*. I would allow for in-vivo potency differences, and for higher plasma concentrations required to pass BBB with sufficient in-vivo neurotrophic effect.

<At the some time they are telling as that drug has excellent bioaveability (oral) and it pass BBB readily!>

My response is not so creative as I simply restate what you know:
They state that the NIP ligands are both orally and systemically active, and that they cross the BBB. Apparently the concentrations capable of doing so with neurotrophic effect are in the reported mg/kg range for systemic dosages. I would further venture higher concs. will be necessary in oral administration. Perhaps the primate studies released soon will address this.

And I agree that 1046 will likely not be used in the US IND. As Zisson's report suggests, more likely it will be the more potent 1234, 1305, 1308 or 1312.


<Did anyone compare two patents (VRTX and GLFD) covering FKBP12 ligands, rotomase enzyme inhibitors? Structures are very similar, some basis unit which are driven from FK 506 structure?>

I would think that FKBP/FK-506 and any derivatives (which the NIP ligands are) would be structurally similar. Do you think that VRTX's rotamase inhibitors also have non-immunosuppresant neuroimmunophilic properties?

But these are questions that would be interesting to hear answers from Guilford on. Perhaps give Angela Webber a call this week.

Regards-

Steve
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