119103-15-0Relevant articles and documents
CEPHEM COMPOUND HAVING CATECHOL GROUP
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Paragraph 0112; 0113, (2013/03/26)
A compound of the formula: wherein X is -N=, -CH=, or the like; W is -CH2- or the like; U is -S- or the like; R1 and R2 are each independently hydrogen, halogen, optionally substituted lower alkyl, or the like; R3/su
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.
Substituent variation in azabicyclic triazole- and tetrazole-based muscarinic receptor ligands
Jenkins,Wadsworth,Bromidge,Orlek,Wyman,Riley,Hawkins
, p. 2392 - 2406 (2007/10/02)
The effect of variation of the 1-azabicyclic substituent on the novel 1,2,3-triazol-4-yl-, 1,2,4-triazol-1-yl-, tetrazol-5-yl-, and tetrazol-2-yl- based muscarinic receptor ligands has been studied, and the exo- azabicyclic[2.2.1]hept-3-yl substituent was found to give the most potent and efficacious compounds. In addition, variation of the second substituent on 1,2,4-triazol-1-yl- and tetrazol-2-yl-based muscarinic receptor ligands has yielded a series of novel compounds with high potencies and efficacies, ranging from full agonists to antagonists. Small lipophilic electron withdrawing substituents give potent but low efficacy compounds, while small polar electron donating substituents give potent and efficacious compounds. The activity of these compounds is described in terms of a model of the receptor involving lipophilic and hydrogen bonding interactions. These compounds provide muscarinic ligands with high potency and a range of efficacies suitable for testing as candidate drugs in the treatment of Alzheimer's disease.
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.
