Lead Optimization and Avoidance of Reactive Metabolite Leading to PCO371, a Potent, Selective, and Orally Available Human Parathyroid Hormone Receptor 1 (hPTHR1) Agonist

Nishimura, Yoshikazu; Esaki, Toru; Isshiki, Yoshiaki; Furuta, Yoshiaki; Mizutani, Asuka; Kotake, Tomoya; Emura, Takashi; Watanabe, Yoshiaki; Ohta, Masateru; Nakagawa, Tatsuo; Ogawa, Kotaro; Arai, Shinichi; Noda, Hiroshi; Kitamura, Hidetomo; Shimizu, Masaru; Tamura, Tatsuya; Sato, Haruhiko

doi:10.1021/acs.jmedchem.9b01743

Cited by 19 publications

(20 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, their studies were discontinued due to too weak affinities and efficacies. The third molecule (PCO371) is currently in phase 1 clinical trial as a potential orally available drug candidate for hypoparathyroidism treatment 34 . It is characterized as an orthosteric agonist of PTHR.…”

Section: Discussionmentioning

confidence: 99%

Precise druggability of the PTH type 1 receptor

et al. 2021

View full text Add to dashboard Cite

Class B G protein-coupled receptors (GPCRs) are notoriously difficult to target by small molecules because their large orthosteric peptide-binding pocket embedded deep within the transmembrane domain limits the identification and development of non-peptide small molecule ligands. Using the parathyroid hormone type 1 receptor (PTHR) as a prototypic class B GPCR target, and a combination of molecular dynamics simulations and elastic network model-based methods, we demonstrate that PTHR druggability can be effectively addressed. Here we found a key mechanical site that modulates the collective dynamics of the receptor and used this ensemble of PTHR conformers to identify selective small molecules with strong negative allosteric and biased properties for PTHR signaling in cell and PTH actions in vivo . This study provides a computational pipeline to detect precise druggable sites and identify allosteric modulators of PTHR signaling that could be extended to GPCRs to expedite discoveries of small molecules as novel therapeutic candidates.

show abstract

Section: Discussionmentioning

confidence: 99%

Precise druggability of the PTH type 1 receptor

et al. 2021

View full text Add to dashboard Cite

show abstract

“…1 H NMR (CDCl 3 ) δ: 7.29 (1H, d, J = 7.9 Hz), 7.27 (1H, d, J = 7.9 Hz), 7.15 (1H, d, J = 3.0 Hz), 7.05 (1H, t, J = 7.9 Hz), 6.54 (1H, d, J = 3.0 Hz), 4.16 (2H, t, J = 7.0 Hz), 3.64 (2H, t, J = 6.3 Hz), 1.97-1.89 (2H, m), 1.60-1.51 (2H, m), 1.26 (1H, brs). 13…”

Section: -(4-bromo-1h-indol-1-yl)butan-1-ol (7 H)mentioning

confidence: 99%

Synthesis and Biological Evaluations of Novel Human Parathyroid Hormone 1 Receptor (hPTHR1) Agonists Bearing Bicyclic Aromatic Moiety

Nishimura,

Esaki,

Isshiki

et al. 2024

ChemMedChem

Self Cite

View full text Add to dashboard Cite

We have previously shown that the small molecule hPTHR1 agonist PCO371 (1) orally and dose‐dependently induces PTH‐like calcemic and hypophostemic activity in thyroparathyroidectomized rats. Compound 2a, bearing a bicyclic aromatic ring, was identified as a novel hPTHR1 agonist during hit to lead modification. It showed moderate PTHR1 agonistic activity with an EC20 value of 15 μM, and its metabolic stability in human liver microsome (hLM) as well as its solubility in phosphate buffer (PPb) and Fasted state simulated intestinal fluid (FaSSIF) were found to be poor. As results of the initial derivatization of 2a, we identified the indole derivatives as another scaffold. In this article, we report on the structure‐activity relationship (SAR), structure‐metabolism relationship (SMR), and structure‐solubility relationship (SSR) of bicyclic aromatic derivatives, and the in vivo efficacy of 2j.

show abstract

“…( 90 ) It increases serum calcium and decreases serum phosphorus in thyroparathyroidectomized rats. ( 91 ) This study has been terminated due to increases in liver enzymes in humans. (AAK, personal communication with Chugai).…”

Section: Emerging Therapies For Hypoptmentioning

confidence: 99%

Management of Hypoparathyroidism

Khan

Guyatt

Ali

et al. 2020

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

Hypoparathyroidism (HypoPT) is a rare disorder characterized by hypocalcemia in the presence of a low or inappropriately normal parathyroid hormone level. HypoPT is most commonly seen after neck surgery, which accounts for approximately 75% of cases, whereas approximately 25% have HypoPT due to nonsurgical causes. In both groups of patients, conventional therapy includes calcium and active vitamin D analogue therapy aiming to maintain serum calcium concentration in the low normal or just below the normal reference range and normalize serum phosphorus, magnesium concentrations, and urine calcium levels. The limitations of conventional therapy include wide fluctuations in serum calcium, high pill burden, poor quality of life, and renal complications. Parathyroid hormone (PTH) replacement therapy may improve the biochemical profile in those in whom conventional therapy proves unsatisfactory. Based on a systematic review and meta‐analysis of the literature, the panel made a graded recommendation suggesting conventional therapy as first line therapy rather than administration of PTH (weak recommendation, low quality evidence). When conventional therapy is deemed unsatisfactory, the panel considers use of PTH. Because pregnancy and lactation are associated with changes in calcium homeostasis, close monitoring is required during these periods with appropriate adjustment of calcium and active vitamin D analogue therapy to ensure that serum calcium remains in the mid to low normal reference range in order to avoid maternal and fetal complications. Emerging therapies include molecules with prolonged PTH action as well as different mechanisms of action that may significantly enhance drug efficacy and safety. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

show abstract

Lead Optimization and Avoidance of Reactive Metabolite Leading to PCO371, a Potent, Selective, and Orally Available Human Parathyroid Hormone Receptor 1 (hPTHR1) Agonist

Cited by 19 publications

References 16 publications

Precise druggability of the PTH type 1 receptor

Precise druggability of the PTH type 1 receptor

Synthesis and Biological Evaluations of Novel Human Parathyroid Hormone 1 Receptor (hPTHR1) Agonists Bearing Bicyclic Aromatic Moiety

Management of Hypoparathyroidism

Contact Info

Product

Resources

About