AC265347的新一代类似物作为钙敏感受体的正变构调节剂：手性中心结构修饰的药理学研究
Next-Generation Analogues of AC265347 as Positive Allosteric Modulators of the Calcium-Sensing Receptor: Pharmacological Investigation of Structural Modifications at the Stereogenic Centre.
作者信息
Dinh Le Vi, Dangerfield Jesse, DeBono Aaron, Keller Andrew N, Josephs Tracy M, Gregory Karen J, Leach Katie, Capuano Ben
机构信息
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia.
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia.
出版信息
Int J Mol Sci. 2025 Mar 13;26(6):2580. doi: 10.3390/ijms26062580.
The calcium-sensing receptor (CaSR) is a validated therapeutic target in the treatment of hyperparathyroidism and related diseases. The CaSR -positive allosteric modulator (PAM), AC265347 (), exhibits a chemically and pharmacologically unique profile compared to current approved CaSR PAM therapeutics. Herein, we report a series of 'next-generation' analogues of AC265347, investigating the impact of structural modifications at the stereogenic centre on CaSR PAM activity. Compounds and featuring the alcohol functional group showed -PAM profiles comparable to , whilst compounds , and devoid of this functionality were 'pure' PAMs with no intrinsic agonism. These novel chemical tools provide an opportunity to explore the therapeutic potential of AC265347-like PAMs as a function of affinity, cooperativity and intrinsic agonism.
钙敏感受体（CaSR）是治疗甲状旁腺功能亢进及相关疾病的一个经过验证的治疗靶点。与目前已获批的CaSR正变构调节剂（PAM）类治疗药物相比，CaSR阳性变构调节剂（PAM）AC265347展现出独特的化学和药理学特性。在此，我们报道了一系列AC265347的“下一代”类似物，研究了手性中心结构修饰对CaSR PAM活性的影响。具有醇官能团的化合物 和 显示出与 相当的PAM特性，而不含该官能团的化合物 、 和 则是“纯”PAM，没有内在激动活性。这些新型化学工具为探索AC265347类PAM作为亲和力、协同性和内在激动活性函数的治疗潜力提供了机会。
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