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
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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DOI：
10.1021/jm9702903
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发表时间：
1997-12-19
影响因子：
7.3
通讯作者：
Riley, GJ
中科院分区：
文献类型：
--
作者：
Bromidge, SM;Brown, F;Riley, GJ
胆碱能功能的丧失被认为与阿尔茨海默型老年性痴呆（SDAT）相关的认知下降有关。该疾病的特征在于位于神经末梢上的毒蕈碱受体的进行性丧失，而突触后毒蕈碱M1受体似乎基本上保持完整。直接作用于突触后受体的毒蕈碱激动剂提供了对抗SDAT中胆碱能缺陷的前景。本研究描述了一系列新颖的氮杂双环毒蕈碱激动剂，其将肟醚或改性肟醚基团作为酯生物电子等排体。通过引入吸电子基团对肟醚官能团进行改性，发现（Z）-N-甲氧基亚氨酰腈基团作为稳定的甲酯生物电子等排体。这最终发现了奎宁环基N-甲氧基亚氨酰腈R-（+）-（Z）-5g，其是目前用于治疗SDAT的III期临床试验中的功能选择性毒蕈碱M1部分激动剂。R-（+）-（Z）-5g的选择性特征可以根据化合物对毒蕈碱受体亚型的相对亲和力、激动剂功效的程度和脑顺应性来合理化。
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 bioisostere. 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.