115595-00-1Relevant articles and documents
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
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.
, p. 4265 - 4280 (2007/10/03)
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.
Comparison of Azabicyclic Esters and Oxadiazoles as Ligands for the Muscarinic Receptor
Orlek, Barry S.,Blaney, Frank E.,Brown, Frank,Clark, Michael S. G.,Hadley, Michael S.,et al.
, p. 2726 - 2735 (2007/10/02)
The link between the cognitive deficit associated with Alzheimer type dementia and the loss of cholinergic function in the disease provides a basis for examining muscarinic agonists as potential therapeutic agents.This paper describes the design and synthesis of novel azabicyclic methyl esters as ligands for the muscarinic receptor.Replacement of the methyl ester by a 3-methyl-1,2,4-oxadiazole ring produces potent metabolically more stable muscarinic agonists capable of penetrating the central nervous system.These compounds generally show improved affinity relativeto the corresponding methyl esters. 3-Methyl-1,2,4-oxadiazole 7b has an affinity 4 times that of acetylcholine.Receptor affinity is discussed in relation to the size and geometry of the azabicyclic ring and the electronic properties of the heteroaromatic ring.
