1.A novel chemoreactive calcilytic for the potential treatment of autosomal dominant hypocalcemia.
Jesse DANGERFIELD ; Aaron DEBONO ; Andrew N KELLER ; Tracy M JOSEPHS ; David M SHACKLEFORD ; Karen J GREGORY ; Katie LEACH ; Ben CAPUANO
Acta Pharmaceutica Sinica B 2025;15(10):5387-5399
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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