Discovery of evocalcet, a next-generation calcium-sensing receptor agonist for the treatment of hyperparathyroidism

[Display omitted] •Optimization from cinacalcet resulted in the discovery of evocalcet.•CYP2D6 inhibition observed in cinacalcet is completely solved in evocalcet.•Gastrointestinal tract symptoms of cinacalcet are drastically improved in evocalcet.•Evocalcet will provide a novel therapeutic option f...

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Published inBioorganic & medicinal chemistry letters Vol. 28; no. 11; pp. 2055 - 2060
Main Authors Miyazaki, Hiroshi, Ikeda, Yousuke, Sakurai, Osamu, Miyake, Tsutomu, Tsubota, Rie, Okabe, Jyunko, Kuroda, Masataka, Hisada, Yutaka, Yanagida, Tetsuya, Yoneda, Hikaru, Tsukumo, Yukihito, Tokunaga, Shin, Kawata, Takehisa, Ohashi, Rikiya, Fukuda, Hajime, Kojima, Koki, Kannami, Ayako, Kifuji, Takayuki, Sato, Naoya, Idei, Akiko, Iguchi, Taku, Sakairi, Tetsuya, Moritani, Yasunori
Format Journal Article
LanguageEnglish
Published OXFORD Elsevier Ltd 15.06.2018
Elsevier
Subjects
Allosteric calcium-sensing receptor agonist
Animals
Calcium-sensing receptor (CaSR)
Chemistry
Chemistry, Medicinal
Chemistry, Organic
Cinacalcet
Cytochrome P-450 Enzyme Inhibitors - chemical synthesis
Cytochrome P-450 Enzyme Inhibitors - chemistry
Cytochrome P-450 Enzyme Inhibitors - pharmacology
Cytochrome P-450 Enzyme System - metabolism
Dose-Response Relationship, Drug
Drug Discovery
Evocalcet
Humans
Hyperparathyroidism
Hyperparathyroidism - drug therapy
Life Sciences & Biomedicine
Models, Molecular
Molecular Structure
Pharmacology & Pharmacy
Physical Sciences
Pyrrolidines - chemical synthesis
Pyrrolidines - chemistry
Pyrrolidines - pharmacology
Rats
Receptors, Calcium-Sensing - agonists
Science & Technology
Structure-Activity Relationship
Evocalcet
Allosteric calcium-sensing receptor agonist
Cinacalcet
Calcium-sensing receptor (CaSR)
Hyperparathyroidism
VITAMIN-D
PTH
SECONDARY HYPERPARATHYROIDISM
IN-VITRO
DIALYSIS PATIENTS
CINACALCET HCL
HEMODIALYSIS-PATIENTS
CARDIOVASCULAR-DISEASE
CALCIFICATION
PRACTICE PATTERNS
Online AccessGet full text

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Abstract [Display omitted] •Optimization from cinacalcet resulted in the discovery of evocalcet.•CYP2D6 inhibition observed in cinacalcet is completely solved in evocalcet.•Gastrointestinal tract symptoms of cinacalcet are drastically improved in evocalcet.•Evocalcet will provide a novel therapeutic option for secondary hyperparathyroidism. The calcium-sensing receptor (CaSR) plays an important role in sensing extracellular calcium ions and regulating parathyroid hormone secretion by parathyroid gland cells, and the receptor is a suitable target for the treatment of hyperparathyroidism. Cinacalcet hydrochloride is a representative CaSR agonist which widely used for the hyperparathyroidism. However, it has several issues to clinical use, such as nausea/vomiting and strong inhibition of CYP2D6. We tried to improve these issues of cinacalcet for a new pharmaceutical agent as a preferable CaSR agonist. Optimization from cinacalcet resulted in the identification of pyrrolidine compounds and successfully led to the discovery of evocalcet as an oral allosteric CaSR agonist. Evocalcet, which exhibited highly favorable profiles such as CaSR agonistic activity and good DMPK profiles, will provide a novel therapeutic option for secondary hyperparathyroidism.
AbstractList The calcium-sensing receptor (CaSR) plays an important role in sensing extracellular calcium ions and regulating parathyroid hormone secretion by parathyroid gland cells, and the receptor is a suitable target for the treatment of hyperparathyroidism. Cinacalcet hydrochloride is a representative CaSR agonist which widely used for the hyperparathyroidism. However, it has several issues to clinical use, such as nausea/vomiting and strong inhibition of CYP2D6. We tried to improve these issues of cinacalcet for a new pharmaceutical agent as a preferable CaSR agonist. Optimization from cinacalcet resulted in the identification of pyrrolidine compounds and successfully led to the discovery of evocalcet as an oral allosteric CaSR agonist. Evocalcet, which exhibited highly favorable profiles such as CaSR agonistic activity and good DMPK profiles, will provide a novel therapeutic option for secondary hyperparathyroidism. (C) 2018 The Authors. Published by Elsevier Ltd.
The calcium-sensing receptor (CaSR) plays an important role in sensing extracellular calcium ions and regulating parathyroid hormone secretion by parathyroid gland cells, and the receptor is a suitable target for the treatment of hyperparathyroidism. Cinacalcet hydrochloride is a representative CaSR agonist which widely used for the hyperparathyroidism. However, it has several issues to clinical use, such as nausea/vomiting and strong inhibition of CYP2D6. We tried to improve these issues of cinacalcet for a new pharmaceutical agent as a preferable CaSR agonist. Optimization from cinacalcet resulted in the identification of pyrrolidine compounds and successfully led to the discovery of evocalcet as an oral allosteric CaSR agonist. Evocalcet, which exhibited highly favorable profiles such as CaSR agonistic activity and good DMPK profiles, will provide a novel therapeutic option for secondary hyperparathyroidism.
[Display omitted] •Optimization from cinacalcet resulted in the discovery of evocalcet.•CYP2D6 inhibition observed in cinacalcet is completely solved in evocalcet.•Gastrointestinal tract symptoms of cinacalcet are drastically improved in evocalcet.•Evocalcet will provide a novel therapeutic option for secondary hyperparathyroidism. The calcium-sensing receptor (CaSR) plays an important role in sensing extracellular calcium ions and regulating parathyroid hormone secretion by parathyroid gland cells, and the receptor is a suitable target for the treatment of hyperparathyroidism. Cinacalcet hydrochloride is a representative CaSR agonist which widely used for the hyperparathyroidism. However, it has several issues to clinical use, such as nausea/vomiting and strong inhibition of CYP2D6. We tried to improve these issues of cinacalcet for a new pharmaceutical agent as a preferable CaSR agonist. Optimization from cinacalcet resulted in the identification of pyrrolidine compounds and successfully led to the discovery of evocalcet as an oral allosteric CaSR agonist. Evocalcet, which exhibited highly favorable profiles such as CaSR agonistic activity and good DMPK profiles, will provide a novel therapeutic option for secondary hyperparathyroidism.
The calcium-sensing receptor (CaSR) plays an important role in sensing extracellular calcium ions and regulating parathyroid hormone secretion by parathyroid gland cells, and the receptor is a suitable target for the treatment of hyperparathyroidism. Cinacalcet hydrochloride is a representative CaSR agonist which widely used for the hyperparathyroidism. However, it has several issues to clinical use, such as nausea/vomiting and strong inhibition of CYP2D6. We tried to improve these issues of cinacalcet for a new pharmaceutical agent as a preferable CaSR agonist. Optimization from cinacalcet resulted in the identification of pyrrolidine compounds and successfully led to the discovery of evocalcet as an oral allosteric CaSR agonist. Evocalcet, which exhibited highly favorable profiles such as CaSR agonistic activity and good DMPK profiles, will provide a novel therapeutic option for secondary hyperparathyroidism.The calcium-sensing receptor (CaSR) plays an important role in sensing extracellular calcium ions and regulating parathyroid hormone secretion by parathyroid gland cells, and the receptor is a suitable target for the treatment of hyperparathyroidism. Cinacalcet hydrochloride is a representative CaSR agonist which widely used for the hyperparathyroidism. However, it has several issues to clinical use, such as nausea/vomiting and strong inhibition of CYP2D6. We tried to improve these issues of cinacalcet for a new pharmaceutical agent as a preferable CaSR agonist. Optimization from cinacalcet resulted in the identification of pyrrolidine compounds and successfully led to the discovery of evocalcet as an oral allosteric CaSR agonist. Evocalcet, which exhibited highly favorable profiles such as CaSR agonistic activity and good DMPK profiles, will provide a novel therapeutic option for secondary hyperparathyroidism.
Author Ikeda, Yousuke
Moritani, Yasunori
Sakurai, Osamu
Sato, Naoya
Iguchi, Taku
Idei, Akiko
Tsukumo, Yukihito
Tsubota, Rie
Kojima, Koki
Miyazaki, Hiroshi
Hisada, Yutaka
Tokunaga, Shin
Kuroda, Masataka
Kawata, Takehisa
Fukuda, Hajime
Yoneda, Hikaru
Kifuji, Takayuki
Yanagida, Tetsuya
Kannami, Ayako
Miyake, Tsutomu
Ohashi, Rikiya
Sakairi, Tetsuya
Okabe, Jyunko
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  surname: Miyazaki
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Issue 11
Keywords Evocalcet
Allosteric calcium-sensing receptor agonist
Cinacalcet
Calcium-sensing receptor (CaSR)
Hyperparathyroidism
VITAMIN-D
PTH
SECONDARY HYPERPARATHYROIDISM
IN-VITRO
DIALYSIS PATIENTS
CINACALCET HCL
HEMODIALYSIS-PATIENTS
CARDIOVASCULAR-DISEASE
CALCIFICATION
PRACTICE PATTERNS
Language English
License This is an open access article under the CC BY license.
Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.
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– name: Elsevier
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Snippet [Display omitted] •Optimization from cinacalcet resulted in the discovery of evocalcet.•CYP2D6 inhibition observed in cinacalcet is completely solved in...
The calcium-sensing receptor (CaSR) plays an important role in sensing extracellular calcium ions and regulating parathyroid hormone secretion by parathyroid...
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SubjectTerms Allosteric calcium-sensing receptor agonist
Animals
Calcium-sensing receptor (CaSR)
Chemistry
Chemistry, Medicinal
Chemistry, Organic
Cinacalcet
Cytochrome P-450 Enzyme Inhibitors - chemical synthesis
Cytochrome P-450 Enzyme Inhibitors - chemistry
Cytochrome P-450 Enzyme Inhibitors - pharmacology
Cytochrome P-450 Enzyme System - metabolism
Dose-Response Relationship, Drug
Drug Discovery
Evocalcet
Humans
Hyperparathyroidism
Hyperparathyroidism - drug therapy
Life Sciences & Biomedicine
Models, Molecular
Molecular Structure
Pharmacology & Pharmacy
Physical Sciences
Pyrrolidines - chemical synthesis
Pyrrolidines - chemistry
Pyrrolidines - pharmacology
Rats
Receptors, Calcium-Sensing - agonists
Science & Technology
Structure-Activity Relationship
Title Discovery of evocalcet, a next-generation calcium-sensing receptor agonist for the treatment of hyperparathyroidism
URI https://dx.doi.org/10.1016/j.bmcl.2018.04.055
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https://www.ncbi.nlm.nih.gov/pubmed/29724589
https://www.proquest.com/docview/2035240329
Volume 28
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