Discovery of novel, potent, and orally bioavailable pyrido[2,3-d][1]benzazepin-6-one antagonists for parathyroid hormone receptor 1

Arai, Yoshikazu; Kiyotsuka, Yohei; Kagechika, Katsuji; Nishi, Tatsuya; Inui, Masaharu; Nagamochi, Masatoshi; Oyama, Kei; Izumi, Masanori

doi:10.1016/j.bmc.2020.115524

Cited by 9 publications

(5 citation statements)

References 10 publications

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“…For instance, both the foliar fungicide fenhexamid 6a (which was approved by EU and used in fruits, vegetables and ornamentals) and the agro-herbicide monalide 6b could be facilely synthesized in a single step in good yields by using the corresponding alkenes and aniline hydrochloride salts as the substrates. The amide 6c , which was the key synthetic intermediate for the synthesis of a PTHR1 antagonist, could be obtained in 62% yield under the standard conditions. Notably, Pd-catalyzed intramolecular hydroaminocarbonylation of 2-(prop-1-en-2-yl)aniline hydrochloride salt proceeded very efficiently to afford 3,3-dimethyloxindole 6d in 95% yield, which was a key synthetic intermediate for the preparation of a series of useful chemicals including pimobendan-type cardiotonic indolidan LY186126, aurora kinase inhibitor AKI-001, an androgen receptor antagonist, and a norepinephrine reuptake inhibitor …”

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confidence: 99%

Palladium-Catalyzed Markovnikov Hydroaminocarbonylation of 1,1-Disubstituted and 1,1,2-Trisubstituted Alkenes for Formation of Amides with Quaternary Carbon

et al. 2021

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Hydroaminocarbonylation of alkenes is one of the most promising yet challenging methods for the synthesis of amides. Herein, we reported the development of a novel and effective Pd-catalyzed Markovnikov hydroaminocarbonylation of 1,1disubstituted or 1,1,2-trisubstituted alkenes with aniline hydrochloride salts to afford amides bearing an α quaternary carbon. The reaction makes use of readily available starting materials, tolerates a wide range of functional groups, and provides a facile and straightforward approach to a diverse array of amides bearing an α quaternary carbon. Mechanistic investigations suggested that the reaction proceeded through a palladium hydride pathway. The hydropalladation and CO insertion are reversible, and the aminolysis is probably the rate-limiting step.

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confidence: 99%

Palladium-Catalyzed Markovnikov Hydroaminocarbonylation of 1,1-Disubstituted and 1,1,2-Trisubstituted Alkenes for Formation of Amides with Quaternary Carbon

et al. 2021

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“…PTH and PTH peptide analogs have been frequently investigated as agonists or an antagonists, but reports on small molecular PTHR1 ligands are rarely seen. [4][5][6][7][8] And while many class A GPCR small molecular ligands have been identified, finding small molecular class B GPCR ligands is still a challenge because of the larger size of endogenous class B ligands. Orally available small molecule agonists targeting Class B GPCRs, such as GLP-1R agonists, are known and currently undergoing Phase II clinical trials.…”

Section: Introductionmentioning

confidence: 99%

“…Based on this efficacy, human PTH(1–34) and PTH(1–84) were launched for the treatment of osteoporosis and hypoparathyroidism, respectively. PTH and PTH peptide analogs have been frequently investigated as agonists or an antagonists, but reports on small molecular PTHR1 ligands are rarely seen [4–8] . And while many class A GPCR small molecular ligands have been identified, finding small molecular class B GPCR ligands is still a challenge because of the larger size of endogenous class B ligands.…”

Section: Introductionmentioning

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

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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.

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“…Parathyroid hormone receptor 1 (PTH1R) is a classic member of class B GPCRs that regulates calcium homeostasis and skeleton development through activation by two endogenous peptide hormones, parathyroid hormone (PTH) and PTH-related peptide (PTHrP) 8,22,23 . PTH1R is a clinically proven target for hypoparathyroidism and osteoporosis, which can be treated with injections of PTH or PTHrP analogs 8,17 .…”

Section: Introductionmentioning

confidence: 99%

A conserved and druggable pocket in class B G protein coupled receptors for orally active small molecule agonists

Xu¹,

Zhao²,

He³

et al. 2023

Preprint

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Class B G protein-coupled receptors (GPCRs), including glucagon-like receptor 1 (GLP-1R) and parathyroid hormone receptor 1 (PTH1R), are peptide hormone receptors and important drug targets. Injectable peptide drugs targeting class B GPCRs have been developed for the treatment of many diseases, including type 2 diabetes, obesity, and osteoporosis, but orally available small molecule drugs are hotly pursued in the field, especially small molecule agonists of GLP-1R and PTH1R. Here we report the first high-resolution structure of the human PTH1R in complex with the stimulatory G protein (Gs) and a small molecule agonist, PCO371, which reveals an unexpected binding mode of PCO371 at the interface of PTH1R and Gs. The binding site of PCO371 is totally different from all binding sites previously reported for small molecules or peptide ligands in GPCRs. Residues that make up the PCO371 binding pocket are mostly conserved in class B GPCRs and a single mutation in PTH type 2 receptor (PTH2R) and two residue mutations in GLP-1R convert these receptors to respond to PCO371 activation. Functional assays reveal that PCO371 is a G-protein biased agonist that is defective in promoting PTH1R-mediated arrestin signaling. Together, these results uncover a distinct binding site for designing small molecule agonists for PTH1R and possible other members of class B GPCRs and define a receptor conformation that is only specific for G protein activation but not arrestin signaling. These insights should facilitate the design of distinct types of class B GPCR small molecule agonists for various therapeutic indications.

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Discovery of novel, potent, and orally bioavailable pyrido[2,3-d][1]benzazepin-6-one antagonists for parathyroid hormone receptor 1

Cited by 9 publications

References 10 publications

Palladium-Catalyzed Markovnikov Hydroaminocarbonylation of 1,1-Disubstituted and 1,1,2-Trisubstituted Alkenes for Formation of Amides with Quaternary Carbon

Palladium-Catalyzed Markovnikov Hydroaminocarbonylation of 1,1-Disubstituted and 1,1,2-Trisubstituted Alkenes for Formation of Amides with Quaternary Carbon

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

A conserved and druggable pocket in class B G protein coupled receptors for orally active small molecule agonists

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