- MONO AND COMBINATION THERAPY OF M1/M4 AGONIST (SABCOMELINE) FOR TREATMENT OF NEGATIVE SYMPTOMS OF SCHIZOPHRENIA
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The invention relates to the use of a functional muscarinic M1/M4 receptor agonist or a pharmaceutically acceptable salt thereof for the treatment of negative symptoms of schizophrenia. It also relates to adjunctive and simultaneous combination therapies for the treatment of negative symptoms of schizophrenia in which the functional muscarinic M1/M4 receptor agonist or a pharmaceutically acceptable salt thereof, in particular sabcomeline or a pharmaceutically acceptable salt thereof and at least one neuroprotective agent, neuroleptic and/or atypical antipsychotic agent are administered adjunctively or simultaneously. The invention also provides methods of treatment of the negative symptoms of schizophrenia utilising such therapies and such adjunctive or simultaneous therapeutic combination therapies, therapeutic combinations for use therein and pharmaceutical compositions comprising them.
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Page/Page column 35
(2008/06/13)
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- MONO AND COMBINATION THERAPY WITH A M1/M4 MUSCARINIC AGONIST (SABCOMELINE) FOR TREATMENT OF COGNITIVE DISORDERS IN SCHIZOPHRENIA
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The invention relates to the use of a functional muscarinic M1/M4 receptor agonist such as the functional muscarinic M1/M4 receptor agonist or a pharmaceutically acceptable salt thereof, in particular sabcomeline or a pharmaceutically acceptable salt thereof in for the treatment of cognitive impairment in schizophrenia and to combination therapies for the treatment of cognitive impairment in schizophrenia which the functional muscarinic M1/M4 receptor agonist or a pharmaceutically acceptable salt thereof, in particular sabcomeline or a pharmaceutically acceptable salt thereof and at least one other neuroprotective agent and/or neuroleptic and/or atypical antipsyhcotic agent are administered adjunctively or simultaneously. The invention provides methods of treatment of cognitive impairment in schizophrenia utilising such therapies and such adjunctive or simultaneous therapeutic combination therapies, therapeutic combinations for use therein and pharmaceutical compositions comprising them.
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Page/Page column 30
(2008/06/13)
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- MONO AND COMBINATION THERAPY WITH M1/M4 MUSCARINIC AGONIST (SABCOMELINE) FOR TREATMENT OF PRODROMAL SYNDROME
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The invention relates to the use of a functional muscarinic M1/M4 agonist or a pharmaceutically acceptable salt thereof to treat prodromal syndrome and in the manufacture of a medicament for the treatment of prodromal syndrome, and to a method of treatment of prodromal syndrome using a functional muscarinic M1/M4 agonist or a pharmaceutically acceptable salt thereof. It also relates to the use of a pharmaceutical composition comprising a functional muscarinic M1/M4 agonist or a pharmaceutically acceptable salt thereof, and at least one cholinergic agent and/or at least one non-cholinergic agent for the treatment of prodromal syndrome, and to a method of treatment of prodromal syndrome by administration of a such a pharmaceutical composition.
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Page/Page column 12
(2010/11/29)
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- COMBINATION OF SABCOMELINE WITH A NEUROLEPTIC AGENT TO TREAT PSYCHOTIC DISORDERS
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The invention relates to adjunctive and simultaneous combination therapies for the treatment of psychotic disorders in which sabcomeline or a pharmaceutically acceptable salt thereof and at least one other neuroleptic agent are administered adjunctively or simultaneously. The invention provides methods of treatment of psychotic disorders utilising such adjunctive or simultaneous therapeutic combination therapies, therapeutic combinations for use therein and pharmaceutical compositions comprising them.
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Page/Page column 1
(2008/06/13)
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- Design of [R-(Z)]-(+)-α-(methoxyimino)-1-azabicyclo[2.2.2]octane-3- acetonitrile (SB 202026), a functionally selective azabicyclic muscarinic M1 agonist incorporating the N-methoxy imidoyl nitrile group as a novel ester bioisostere
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Loss of cholinergic function is believed to be implicated in the cognitive decline associated with senile dementia of the Alzheimer type (SDAT). The disease is characterized by progressive loss of muscarinic receptors located on nerve terminals while postsynaptic muscarinic M1 receptors appear to remain largely intact. Muscarinic agonists acting directly on postsynaptic receptors offer the prospect of countering the cholinergic deficit in SDAT. This study describes a novel series of azabicyclic muscarinic agonists, which incorporate an oxime ether or modified oxime ether group as an ester bioisotere. Modification of the oxime ether function by the introduction of electron withdrawing groups led to the finding that the (Z)-N-methoxy imidoyl nitrile group serves as a stable methyl ester bioisostere. This culminated in the discovery of the quinuclidinyl N-methoxy imidoyl nitrile (R)-(+)-(Z)-5g which is a functionally selective muscarinic M1 partial agonist currently in phase III clinical trials for the treatment of SDAT. The selective profile of R-(+)- (Z)-5g can be rationalized in terms of the relative affinity of the compound at muscarinic receptor subtypes, the degree of agonist efficacy, and brain penetrancy.
- Bromidge, Steven M.,Brown, Frank,Cassidy, Frederick,Clark, Michael S. G.,Dabbs, Steven,Hadley, Michael S.,Hawkins, Julie,Loudon, Julia M.,Naylor, Christopher B.,Orlek, Barry S.,Riley, Graham J.
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p. 4265 - 4280
(2007/10/03)
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- Synthesis and properties of [R-(Z)]-(+)-α-(1-azabicyclo[2.2.2]oct-3-yl)-α- (methoxyimino)acetonitrile, a novel functionally selective muscarinic partial agonist
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The (Z)-N-methoxy imidoyl nitrile functionality is a novel methyl ester bioisostere, which, when substituted onto the quinuclidine ring system gives the title compound 1, a stable, brain penetrant and functionally selective muscarinic partial agonist; X-ray studies confirm the configurational assignment and reveal that the imino and cyano bond lengths are consistent with those expected for formal double and triple bonds respectively.
- Bromidge,Cassidy,Clark,Eggleston,Oriek
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p. 2189 - 2190
(2007/10/02)
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- AZABICYLO OXIME COMPOUNDS
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A compound of formula (I) or a pharmaceutically acceptable salt thereof: STR1 wherein R 1 represents STR2 in which each of p and q independently represents an integer of 2 to 4, r represents an integer of 2 to 4, s represents 1 or 2 and t represents 0 or 1; R 2 is a group OR 4, where R 4 is C 1-4 alkyl, C. sub.2-4 alkenyl, C 2-4 alkynyl, a group OCOR 5 where R 5 is hydrogen or R 4, or a group NHR 6 or NR 7 R 8 where R 6, R 7 and R 8 are independently C 1-2 alkyl; and R 3 is chloro, fluoro, bromo, cyclopropyl, C 1-3 alkyl substituted by one, two or three halogen atoms, or R 3 is a group (CH. sub.2) n R 9 where R 9 is--CN,--OH,--OCH 3,--SH,--SCH 3,--C CH or--CH=CH 2 and n is O or 1, with the proviso that when n is 0, R 9 is not--OH or--SH.
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