SNAP/LLY migraine trials - 5HT-1F agonist.
Talk about low-key - SNAP filed an 8-K (excerpted below) but didn't
seem to put out a press release. This is the first time I've seen the name of the drug rather than only its general description specified.
The triptan migraine field is very crowded, although none of the existing drugs is pefect. The other drugs are typically 5HT-1B/1D agonists, although not completely selective. Sumatriptan apparently also binds to 1F.
The only other 1F work seems to be from Lilly itself. Only a few
abstracts on Medline, which I have included below the 8-K
Item 5. Other Events
Synaptic Pharmaceutical Corporation (the "Company"), in
collaboration
with Eli Lilly and Company ("Lilly"), is currently conducting drug
discovery programs focused on a number of serotonin receptor
subtypes and therapeutic applications. One of such programs is
focused on the identification and development of compounds that
are selective agonists of the serotonin 1F receptor subtype for
the treatment of migraine. Lilly recently completed a Phase II
clinical study in Europe with LY334370, a compound identified as
part of this program. This clinical study tested a wide dose range and
final analysis of the data generated in this study is in progress. An
investigational new drug request (an "IND") with respect to LY334370
was filed with the United States Food and Drug Administration in
January 1998. Lilly is conducting two additional Phase II clinical
studies with respect to LY334370 in the United States in an effort
to further define the dose response relationship and to
explore formulation options.
To date, in the limited Phase II clinical studies,
LY334370 was observed to reduce or eliminate migraine
pain. According to Lilly, no cardiovascular side effects have
been observed, although at certain higher doses side effects such as
asthenia, dizziness and/or somnolence were observed. In the ongoing
Phase II clinical studies, Lilly will attempt to define the doses
which result in efficacy and compare those doses to the doses
resulting in side effects. The efficacy and side effect profile of
LY334370 will then be compared to other currently available migraine
treatments. Lilly has informed the Company that it expects to make a
decision on whether to proceed to Phase III clinical trials by the
end of 1998 and that its decision will be based on the outcome of the
three Phase II clinical studies.
Life Sci 1997;61(21):2117-2126
Characterization of LY344864 as a pharmacological tool to study 5-HT1F
receptors: binding affinities, brain penetration and activity in the
neurogenic dural inflammation model of migraine.
Phebus LA, Johnson KW, Zgombick JM, Gilbert PJ, Van Belle K, Mancuso
V, Nelson DL, Calligaro DO, Kiefer AD Jr, Branchek TA, Flaugh ME Eli
Lilly and Co., Lilly Corporate Center, Indianapolis, Indiana 46285,
USA. lphebus@lilly.com
LY344864 is a selective receptor agonist with an affinity of 6 nM (Ki)
at the recently cloned 5-HT1F receptor. It possesses little affinity
for the 56 other serotonergic and non-serotonergic neuronal binding
sites examined. When examined for its ability to inhibit
forskolin-induced cyclic AMP accumulation in cells stably transfected
with human 5-HT1F receptors, LY344864 was shown to be a full agonist
producing an effect similar in magnitude to serotonin itself. After an
intravenous dose of 1 mg/kg, rat plasma LY344864 levels declined with
time whereas brain cortex levels remained relatively constant for the
first 6 hours after injection. Oral and intravenous LY344864
administration potently inhibited dural protein extravasation caused
by electrical stimulation of the trigeminal ganglion in rats. Taken
together, these data demonstrate that LY344864 is a selective 5-HT1F
receptor agonist that can be used to explore both the in vitro and in
vivo functions of this receptor.
PMID: 9395253, UI: 98055631
Neuroreport 1997 Jul 7;8(9-10):2237-2240
5-HT1F receptor agonists inhibit neurogenic dural inflammation in
guinea pigs.
Johnson KW, Schaus JM, Durkin MM, Audia JE, Kaldor SW, Flaugh ME,
Adham N, Zgombick JM, Cohen ML, Branchek TA, Phebus LA Eli Lilly &
Co., Lilly Corporate Center, Indianapolis, IN 46285, USA.
The serotonin (5-HT) receptor subtype mediating inhibition of
neurogenic dural inflammation in guinea pigs was investigated using a
series of serotonin agonists with differing affinities for the 5-HT1B,
5-HT1D and 5-HT1F receptors. When agonist potencies for inhibiting
neurogenic inflammation were compared with affinities for these
receptor subtypes, a significant positive correlation was seen only
with the 5-HT1F receptor. The potency of agonists in inhibiting
adenylate cyclase in cells transfected with human 5-HT1F receptor was
also highly correlated with their potency in the animal model of
migraine. In situ hybridization demonstrated 5-HT1F receptor mRNA in
guinea pig trigeminal ganglion neurons. These data suggest that the
5-HT1F receptor is a rational target for migraine therapeutics.
PMID: 9243618, UI: 97387598
----------------------------------------------------------------------
Cephalalgia 1996 Aug;16(5):317-322
Autoradiographic distribution of [3H]sumatriptan-binding sites in
post-mortem human brain.
Pascual J, del Arco C, Romon T, del Olmo E, Castro E, Pazos A
Department of Physiology and Pharmacology, University Hospital Marques
de Valdecilla, University of Cantabria, Spain.
The anatomical distribution of [3H]sumatriptan-binding sites was
analysed in brain tissue sections from 11 subjects. Relevant
concentrations of [3H]sumatriptan-binding sites were seen in areas
such as visual cortex > locus niger > globus pallidus > layers IV-V of
the frontal cortex > subiculum > entorhinal cortex > nucleus tractus
solitarius > nucleus trigeminalis caudalis. This distribution of
[3H]sumatriptan-binding sites in the human brain shows some
differences when compared with that of 5HT1D receptors, confirming
that, besides 5HT1D, sumatriptan also binds to 5HT1F receptor subtype.
Some species differences are evident between the distribution of
[3H]sumatriptan-binding sites in the human brain and that reported for
guinea-pig and rat brains, emphasizing that caution is needed in
extrapolating experimental data from animals to humans. Furthermore,
these data help to explain some of the therapeutic actions of
sumatriptan. The remarkable levels of binding found in areas as
nucleus tractus solitarius and nucleus trigeminalis caudalis suggest
that in migraine attacks sumatriptan could exert its specific
anti-emetic effects and, partly at least, induce analgesia by directly
acting over these brain nuclei.
Comments:
Comment in: Cephalalgia 1996 Aug;16(5):287-8
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