A novel chemoreactive calcilytic for the potential treatment of autosomal dominant hypocalcemia.
10.1016/j.apsb.2025.07.044
- Author:
Jesse DANGERFIELD
1
;
Aaron DEBONO
1
;
Andrew N KELLER
2
;
Tracy M JOSEPHS
2
;
David M SHACKLEFORD
3
;
Karen J GREGORY
2
;
Katie LEACH
2
;
Ben CAPUANO
1
Author Information
1. Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, VIC 3052, Australia.
2. Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, VIC 3052, Australia.
3. Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, VIC 3052, Australia.
- Publication Type:Journal Article
- Keywords:
Autosomal dominant hypocalcemia;
Calcilytic;
Calcium-sensing receptor;
Chemoreactive;
Irreversible
- From:
Acta Pharmaceutica Sinica B
2025;15(10):5387-5399
- CountryChina
- Language:English
-
Abstract:
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.
