LBSAT142 Discovery And Characterization Of A Potent And Orally Bioavailable Parathyroid Hormone Receptor Type-1 (PTHR1) Antagonist For The Treatment Of Hypercalcemia
Authors: Rico-Bautista Elizabeth , Pontillo Joseph , Wang Shimiao , Antwan Agnes S , Arroyo Pablo , Fleck Beth , Fowler Melissa A , Reinhart Greg , Johns Michael A , Kusnetzow Ana K , Zhu Yun Fei , Markison Stacy , Betz Stephen F 
Published: November 2022

Abstract
Hypercalcemia is a common disorder defined as a serum calcium concentration higher than the normal range of 8.5 - 10.5 mg/dL. The most common causes of hypercalcemia are over-secretion of parathyroid hormone (PTH) from one or more enlarged parathyroid glands, which can lead to primary hyperparathyroidism (PHPT), or over-secretion of parathyroid hormone related protein (PTHrP) from a cancerous tumor, which leads to humoral hypercalcemia of malignancy (HHM). PTH is an 84 amino acid peptide that regulates calcium and phosphate homeostasis through activation of its receptor, PTHR1. PTHrP has close homology to the N-terminal region of PTH and also activates PTHR1, inducing similar biological actions. Activation of PTHR1, a class B G-protein coupled receptor expressed in bone and kidney, leads to an increase in cAMP and PKA activation, inducing gene expression changes of important modulators of bone homeostasis. In the kidney, it increases renal phosphate excretion and calcium reabsorption. Hyperactivation of PTHR1 due to high levels of either PTH or PTHrP results in increased calcium release from the bone matrix, as well as increased calcium reabsorption in the kidney, causing hypercalcemia. Surgery is the first line therapy for PHPT, but patients that cannot or choose not to have surgery are prescribed calcimimetics and/or bisphosphonates. Calcimimetics decrease circulating calcium levels but have no effect on bone homeostasis, while bisphosphonates improve bone homeostasis but have little effect on circulating calcium levels. HHM patients are prescribed bisphosphonates or denosumab, both of which possess undesirable side effects. We hypothesize that blocking PTH/PTHrP action via a PTHR1 antagonist may provide an improved therapeutic mechanism to treat PHPT and HHM, and potentially other diseases of hypercalcemia. Using an iterative medicinal chemistry approach, Crinetics has identified several nonpeptide PTHR1 antagonists via both binding and functional in vitro assays. One of these compounds, Antagonist 1 (ANT-1), has low nanomolar binding affinity for both human and rat PTHR1 and is potent in human, monkey, rat, mouse and canine PTHR1 functional antagonist assays in vitro. ANT-1 has good oral exposure in preclinical species and desirable drug-like properties, including lack of inhibition of cytochromes P450 and the hERG ion channel, and stability in liver microsomes. In rat models of PTH- and PTHrP-induced hypercalcemia, ANT-1 dose-dependently suppresses ionized blood calcium, providing support that a nonpeptide PTH antagonist has potential use as an effective therapeutic for hypercalcemia caused by PHPT and HHM. Currently, ANT-1 and other potential candidate molecules are being evaluated in a battery of safety studies to select the optimal molecule(s) suitable for evaluation in human clinical trials.
Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.