一种用于常染色体显性低钙血症潜在治疗的新型化学反应溶钙剂

IF 14.6 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B Pub Date : 2025-10-01 DOI:10.1016/j.apsb.2025.07.044

Jesse Dangerfield , Aaron DeBono , Andrew N. Keller , Tracy M. Josephs , David M. Shackleford , Karen J. Gregory , Katie Leach , Ben Capuano

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引用次数: 0

摘要

常染色体显性低钙血症（ADH） 1型和2型是由功能变异的获得引起的钙稳态紊乱。钙敏感受体（CaSR）是一种C类GPCR，通过抑制甲状旁腺激素（PTH）分泌和促进肾中Ca2+和其他盐的排泄来恢复生理正常的Ca2+o浓度，从而对细胞外钙（Ca2+o）升高做出反应。CaSR阴性变构调节剂（NAMs）可瞬时升高ADH1患者的PTH水平，使Ca2+o浓度恢复到生理正常范围。在此，我们披露了CaSR的化学反应性NAM （ATF936-NCS, 4）的发现，该NAM (i)具有耐洗性，表明不可逆受体结合，（ii）在体内刺激PTH的长时间释放。这种“一流”的化学探针将为开发治疗ADH的长效NAMs提供宝贵的见解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

A novel chemoreactive calcilytic for the potential treatment of autosomal dominant hypocalcemia

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A novel chemoreactive calcilytic for the potential treatment of autosomal dominant hypocalcemia

Autosomal dominant hypocalcemia (ADH) type 1 and 2 are disorders of calcium homeostasis caused by gain of function variants. The calcium-sensing receptor (CaSR) is a class C GPCR that responds to elevated extracellular calcium (Ca²⁺_o) by inhibiting parathyroid hormone (PTH) secretion and promoting renal excretion of Ca²⁺ and other salts to restore physiologically normal Ca²⁺_o concentrations. CaSR negative allosteric modulators (NAMs) transiently raise PTH levels in individuals with ADH1, restoring Ca²⁺_o concentration to a physiological normal range. Herein we disclose the discovery of a chemoreactive NAM (ATF936-NCS, 4) for the CaSR that (i) is wash-resistant indicative of irreversible receptor binding and (ii) stimulates prolonged PTH release in vivo. This ‘first-in-class’ chemical probe will provide invaluable insight towards the development of longer acting NAMs for the treatment of ADH.

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来源期刊

Acta Pharmaceutica Sinica. B Pharmacology, Toxicology and Pharmaceutics-General Pharmacology, Toxicology and Pharmaceutics

CiteScore

22.40

自引率

5.50%

发文量

1051

审稿时长

19 weeks

期刊介绍： The Journal of the Institute of Materia Medica, Chinese Academy of Medical Sciences, and the Chinese Pharmaceutical Association oversees the peer review process for Acta Pharmaceutica Sinica. B (APSB). Published monthly in English, APSB is dedicated to disseminating significant original research articles, rapid communications, and high-quality reviews that highlight recent advances across various pharmaceutical sciences domains. These encompass pharmacology, pharmaceutics, medicinal chemistry, natural products, pharmacognosy, pharmaceutical analysis, and pharmacokinetics. A part of the Acta Pharmaceutica Sinica series, established in 1953 and indexed in prominent databases like Chemical Abstracts, Index Medicus, SciFinder Scholar, Biological Abstracts, International Pharmaceutical Abstracts, Cambridge Scientific Abstracts, and Current Bibliography on Science and Technology, APSB is sponsored by the Institute of Materia Medica, Chinese Academy of Medical Sciences, and the Chinese Pharmaceutical Association. Its production and hosting are facilitated by Elsevier B.V. This collaborative effort ensures APSB's commitment to delivering valuable contributions to the pharmaceutical sciences community.