Discovery and Characterization of Novel, Potent, Non-Peptide Parathyroid Hormone-1 Receptor Antagonists

Abstract

A 1,3,4-benzotriazepine was identified as a suitable lead in our effort toward obtaining a non-peptide parathyroid hormone-1 receptor (PTH1R) antagonist. A process of optimization afforded derivatives displaying nanomolar PTH1R affinity, a representative example of which behaved as a PTH1R antagonist in cell-based cyclic adenosine monophosphate (cAMP) assays, with selectivity over PTH2 receptors.

Role of Parathyroid Hormone-Related Protein in the Decreased Osteoblast Function in Diabetes-Related Osteopenia

“…Interestingly, chronic exposure of MC3T3-E1 cells to either neutralizing PTHrP antiserum C13 (at 1:100 dilution) or two PTH1R antagonists, the well-characterized PTHrP (7-34) peptide (21), and the nonpeptide PTH1R antagonist JB1421 (38), each at 1 M, in normal glucose medium mimicked the inhibitory effect of the hyperosmotic medium on OSX, OC, and VEGF expression (Fig. 5).…”

International Union of Basic and Clinical Pharmacology. XCIII. The Parathyroid Hormone Receptors—Family B G Protein–Coupled Receptors

“…Several small-molecule ligands have been identified for the PTHR1 but most of these function as weak antagonists (Carter et al, 2007;McDonald et al, 2007), and only one compound, called AH-3960 (dibutyl-diaminomethylenepyrimidine-2,4, 6-trione), exhibited agonist activity, albeit the potency of the compound for stimulating cAMP formation in cells was in the micromolar range compared with the low-nanomolar potency observed for PTH(1-34) (Rickard et al, 2006) (Table 2). The mechanisms of action of the compound ligands identified so far for the PTHR1 have not been determined, and so it is not clear whether they bind to the same or overlapping binding sites in the receptor as that used by PTH peptide ligands or to some other site and thereby function as allosteric modulators (Hoare, 2007) H)-one], was found by screening for the capacity to inhibit binding of a modified PTH(1-14) radioligand analog to the PTHR1, and so this compound likely binds to the same TMD receptor site used by the N-terminal pharmacophore of the PTH agonist ligand (Carter et al, 2007).…”

Mechanisms of Humoral Hypercalcemia of Malignancy in Leukemia/Lymphoma

“…The pharmacological behavior of SW106 is not yet completely understood. A similar compound, 1,3,4-benzotriazepine was identified and serves as a base molecule to develop non-peptide PTH1R antagonist derivatives (McDonald et al, 2007). Using a radioligand binding assay that measures cAMP production, N-1 anilino-substituted compounds were identified that have up to a 1000-fold more potency at inhibiting PTH1R compared to the original compound.…”