Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-07-20
2001-11-27
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S221000
Reexamination Certificate
active
06323198
ABSTRACT:
The present invention provides a method of treatment for enhancing cognition (for example in the treatment of dementing illnesses such as Alzheimer's disease), compositions useful in such a method and methods of manufacturing medicaments for said purpose.
A number of dementing illnesses such as Alzheimer's disease are characterised by a progressive deterioration in cognition in the sufferer. It would clearly be desirable to enhance cognition in subjects desirous of such treatment, for example for subjects suffering from a dementing illness.
It has been reported by McNamara and Skelton in Psychobiology, 21:101-108, that the benzodiazepine receptor inverse agonist &bgr;-CCM enhanced spatial learning in the Morris watermaze. However, &bgr;-CCM and other conventional benzodiazepine receptor inverse agonists are proconvulsant which makes it clear that they cannot be used as cognition enhancing agents in humans.
However, we have now discovered that it is possible to obtain medicaments which have cognition enhancing effects, but which do not possess proconvulsant effects previously described with benzodiazapine receptor inverse agonists.
The benzodiazepine receptor site is in the GABA
A
receptor, a structure that is generally accepted to be pentameric, with an integral chloride ion channel being formed by the second transmembrane domain of each of the five subunits. A family of 14 GABA
A
receptor subunits have been identified in mammalian brain using modern molecule cloning techniques, namely the &agr;
1
, &agr;
2
, &agr;
3
, &agr;
4
, &agr;
5
, &agr;
6
, &bgr;
1
, &bgr;
2
, &bgr;
3
, &ggr;
1
, &ggr;
2
, &ggr;
3
, &dgr; and &phgr; subunits. Selection of five subunits from a possible repetoir of 14 allows for a multiplicity of possible combinations but the number of subtypes which occur and the extent of GABA
A
receptor heterogeneity remains unknown. When referred to hereinafter as a &agr;
1
, &agr;
2
, &agr;
3
, &agr;
5
or &agr;
6
receptor, reference is of course made to the GABA
A&agr;1
, GABA
A&agr;2
, GABA
A&agr;3
, GABA
A&agr;5
and GABA
A&agr;6
It has now been discovered that use of an &agr;
5
receptor inverse agonist which is relatively free of certain activity at &agr;
1
and/or &agr;
2
and/or &agr;
3
receptor binding sites can be used to provide a medicament which is useful for enhancing cognition but which is not proconvulsant.
Accordingly the present invention provides a method of enhancing cognition without producing convulsions which method comprises administering to the subject in need thereof a cognition enhancing amount of a compound which is an &agr;
5
receptor inverse agonist which is not a receptor agonist or receptor inverse agonist at &agr;
1
and/or &agr;
2
and/or &agr;
3
receptors said amount being sufficient to enhance cognition without producing convulsions.
The method will be applied to a mammal, most aptly to a human and preferably to a human suffering from a dementing illness such as Alzheimer's disease.
Thus the compound employed will bind as an inverse agonist to &agr;
5
receptors at concentrations at which no significant agonist or inverse agonist binding occurs to &agr;
1
receptors. More suitably the compound will bind as an inverse agonist to &agr;
5
receptors at concentrations at which no significant agonist or inverse agonist binding occurs to &agr;
1
and &agr;
2
receptors. And most suitably the compound will bind as an inverse agonist to &agr;
5
receptors at concentrations at which no significant agonist or inverse agonist binding occurs to &agr;
1
, &agr;
2
, and &agr;
3
receptors.
The inverse agonist binding at &agr;
5
may be partial (ie the compound may be a partial agonist) but a full inverse agonist at &agr;
5
is preferred. Similarly the compound should not be a full or partial agonist or inverse agonist at the other receptors.
The compounds employed may have antagonist binding at &agr;
1
, &agr;
2
, &agr;
3
and at &agr;
6
if desired as such binding will not adversely effect the operation of the method of this invention. When relative binding to the various receptors is concerned it is only the inverse agonist or agonist binding that is considered.
In general such compounds will bind at least 10 fold better to &agr;
5
receptors than &agr;
1
receptors, that is the compound will be at least 10 fold selective for &agr;
5
containing receptors over &agr;
1
containing receptors.
Aptly the compound for use in the invention at least 10 fold selective for &agr;
5
containing receptors over &agr;
1
and &agr;
2
containing receptors, more aptly at least 10 fold selective for &agr;
5
containing receptors over &agr;
1
, &agr;
2
and &agr;
3
containing receptors and most aptly at least 10 fold selective for &agr;
5
containing receptors over &agr;
1
, &agr;
2
, &agr;
3
and &agr;
6
containing receptors.
Favourably the compound for use in the invention at least 25 fold selective for &agr;
5
containing receptors over &agr;
1
containing receptors, for example 25 fold selective for &agr;
5
containing receptors over &agr;
1
and &agr;
2
containing receptors, more aptly at least 25 fold selective for &agr;
5
containing receptors over &agr;
1
, &agr;
2
and &agr;
3
containing receptors and most aptly at least 25 fold selective for as containing receptors over &agr;
1
, &agr;
2
, &agr;
3
and &agr;
6
containing receptors.
Preferably the compound for use in the invention at least 50 fold selective for &agr;
5
containing receptors over &agr;
1
containing receptors, for example &agr;
1
and &agr;
2
containing receptors, more aptly at least 50 fold selective for &agr;
5
containing receptors over &agr;
1
, &agr;
2
and &agr;
3
containing receptors and most aptly at least 50 fold selective for &agr;
5
containing receptors over &agr;
1
, &agr;
2
, &agr;
3
and &agr;
6
containing receptors.
With advantage, the compound for use in the invention will be at least 100 fold selective for &agr;
5
containing receptors over &agr;
1
receptors.
The favoured method of this invention has the additional advantage of being able to enhance cognition without inducing unwanted anxiogenic effects.
A favoured receptor for determining &agr;
5
binding is the &agr;
5
&bgr;
3
&ggr;
2
receptor. A favoured receptor for determining the &agr;1 binding is the &agr;
1
&bgr;
3
&ggr;
2
receptor. A favoured receptor for determining &agr;
2
binding is the &agr;
2
&bgr;
3
&ggr;
2
receptor. A favoured receptor for determining &agr;
3
binding is the &agr;
3
&bgr;
3
&ggr;
2
receptor. A favoured receptor for determining the &agr;
6
binding is the &agr;
6
&bgr;
3
&ggr;
2
receptor.
Receptors are described in International Patent Application No WO 92/22652 and WO94/13799.
The compounds for use in the method of this invention may be identified by screening against the above identified receptors using techniques known in the art. Favoured techniques include those described in Goeders et al (see hereinafter).
The determination of whether the compounds are receptor agonists, receptor partial agonists or receptor inverse agonists can likewise be determined using techniques known in the art. Favoured techniques include those described in Wafford et al (see hereinafter).
Particularly suitable compounds for use in this invention will have a Ki value (nM) against the &agr;
5
&bgr;
3
&ggr;
2
receptor of less than 5, more suitably less than 2 and most suitably less than 1, for example about 0.5.
Particularly suitable compounds for use in this invention will have a Ki value (nM) against the &agr;
1
&bgr;
3
&ggr;
2
receptor of greater than 10, more suitably greater than 20, most suitably greater than 40, for example about 50.
Particularly suitable compounds for use in this invention will have a Ki value (nM) against the &agr;
2
&bgr;
3
&ggr;
2
receptor of greater than 5, more suitably greater than 10, most suitably greater than 20, for example about 25.
Particularly suitable compounds for use in this invention will have a Ki value (nM) against the &agr;
3
&bgr;
3
&ggr;
2
receptor of greater than 5, more suitably greater than 10, most
Fay Zohreh
Lee Shuy Muk
Merck Sharp & Dohme Limited
Rose David L.
LandOfFree
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