| To: Czechsinthemail who wrote () | 7/17/1999 1:29:00 PM | | From: scaram(o)uche | | | |
J Pharmacol Exp Ther 1999 Jul;290(1):170-81
SIB-1757 and SIB-1893: selective, noncompetitive antagonists of
metabotropic glutamate receptor type 5.
Varney MA, Cosford ND, Jachec C, Rao SP, Sacaan A, Lin FF, Bleicher L, Santori EM, Flor PJ, Allgeier H,
Gasparini F, Kuhn R, Hess SD, Veli elebi G, Johnson EC
SIBIA Neurosciences, Inc., La Jolla, California.
[Medline record in process]
Cell lines expressing the human metabotropic glutamate receptor subtype 5a (hmGluR5a) and hmGluR1b were used as targets
in an automated high-throughput screening (HTS) system that measures changes in intracellular Ca2+ ([Ca2+]i) using
fluorescence detection. This functional screen was used to identify the mGluR5-selective antagonist, SIB-1757
[6-methyl-2-(phenylazo)-3-pyridinol], which inhibited the glutamate-induced [Ca2+]i responses at hmGluR5 with an IC50 of
0.37 &mgr;M compared with an IC50 of >100 &mgr;M at hmGluR1. Schild analysis demonstrated a noncompetitive
mechanism of inhibition. Pharmacophore mapping was used to identify an additional compound, SIB-1893
[(E)-2-methyl-6-(2-phenylethenyl)pyridine], which was also shown to block glutamate-induced increases in [Ca2+]i at
hmGluR5 with an IC50 of 0.29 &mgr;M compared with an IC50 of >100 &mgr;M at hmGluR1. SIB-1757 and SIB-1893
showed little or no activity when tested for agonist and antagonist activity at the other recombinant human mGluR subtypes,
alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, kainate, and N-methyl-D-aspartate receptors. In rat neonatal
brain slices, SIB-1757 and SIB-1893 inhibited (S)-3,5-dihydroxyphenylglycine (DHPG)-evoked inositol phosphate
accumulation in hippocampus and striatum by 60% to 80%, with a potency similar to that observed on recombinant mGluR5.
However, in the cerebellum, a brain region with low mGluR5 expression, SIB-1757 failed to inhibit DHPG-evoked inositol
phosphate accumulation. In cultured rat cortical neurons, SIB-1757 and SIB-1893 largely inhibited DHPG-evoked [Ca2+]i
signals, revealing a population of neurons that were less sensitive to SIB-1757 and SIB-1893. This is the first description of
highly selective, noncompetitive mGluR5 antagonists. These compounds will be useful tools in evaluating the role of mGluR5 in
normal physiology and in animal models of disease. |
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| To: scaram(o)uche who wrote (448) | 7/17/1999 7:26:00 PM | | From: tommysdad | | | |
While wading through the 23 (!!) U.S. patents issued to Sibia in the past year and a half, this one popped up:
patents.uspto.gov
Anyone care to comment on why Sibia has been assigned this patent? Not exactly "neurosciences".
BTW, 23 U.S. patents in a year and a half is unbelievable for a company this size -- more than any other biotech I follow. Very productive group (of both scientists AND attorneys).
TIA |
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| To: tommysdad who wrote (449) | 7/17/1999 8:22:00 PM | | From: scaram(o)uche | | | |
Weird. Priority date looks like '91, however.
>> BTW, 23 U.S. patents in a year and a half is unbelievable for a company this size --
more than any other biotech I follow. Very productive group (of both scientists
AND attorneys). <<
Finally, a second person has noticed.
- g -
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| To: scaram(o)uche who wrote (452) | 7/19/1999 8:50:00 PM | | From: John Metcalf | | | |
{Pfizer ethics} Pfizer is becoming its own Viagra joke, having rocketed off for awhile and staying up longer than expected....
www2.nando.net
Pfizer is pleading guilty in a price-fixing scheme. They continued the illegal practice 15 years, and were only fined $20mm, or $1.3mm per year, to view it coldly. Our regulatory apparatus can be quite reasonable to rent!
From curiosity, I read the litigation sections from PFE's 10-Q and 10-K. More good news! Pfizer's attorneys are way too busy to spend much time with Sibia. If they follow a frequent PFE strategy of extending litigation for years, Sibia won't be hurt by it, being able to practice and license their invention in the meantime.
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| To: scaram(o)uche who wrote (452) | 7/21/1999 9:56:00 AM | | From: scaram(o)uche | | | |
1508Y results negative. Studies insufficiently powered. Lilly gets a year to look at.......... "a trend to significance was noted and significant differences
between doses of altinicline were observed, suggesting a dose-response effect."
biz.yahoo.com |
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