SB-423557

SB-423557 is an orally active small-molecule calcilytic that acts as a negative allosteric modulator of the calcium-sensing receptor (CaSR), leading to transient increases in endogenous parathyroid hormone (PTH) secretion and stimulation of bone formation. It is an ethyl ester prodrug of the more potent free acid SB-423562 (423562, NPS-2143 derivative), designed to be rapidly absorbed and cleaved to SB-423562 in vivo, thereby generating short, PTH-like pulses that favor bone anabolism over resorption in preclinical osteoporosis models. Developed originally by GlaxoSmithKline and later transferred to NPS Pharmaceuticals (subsequently acquired by Takeda), SB-423557 has undergone early clinical evaluation including a phase 2 study in humans, demonstrating transient PTH elevation with a kinetic profile similar to injected recombinant human PTH and bone anabolic effects in ovariectomized rats, and has also been explored for autosomal dominant hypocalcaemia and related CaSR-mediated disorders.