17,20-Lyase inhibitors. Part 4: Design, synthesis and structure-activity relationships of naphthylmethylimidazole derivatives as novel 17,20-lyase inhibitors

Tomohiro Kaku, Nobuyuki Matsunaga, Akio Ojida, Toshimasa Tanaka, Takahito Hara, Masuo Yamaoka, Masami Kusaka, Akihiro Tasaka

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

A novel series of naphthylmethylimidazole derivatives and related compounds have been investigated as selective 17,20-lyase inhibitors. Optimization of the substituent at the 6-position on the naphthalene ring was performed to yield a methylcarbamoyl derivative, which exhibited potent inhibitory activity against human 17,20-lyase and promising selectivity (>200-fold) for 17,20-lyase over CYP3A4. Further modifications of the methylcarbamoyl derivative led to the discovery of the corresponding tricyclic compound, which showed highly potent activity against human 17,20-lyase (IC 50 19 nM) and good selectivity (>1000-fold) for inhibition of 17,20-lyase over CYP3A4. Additional biological evaluation revealed that the tricyclic compound had potent in vivo efficacy in monkeys and favorable pharmacokinetic profiles when administered in rats. Asymmetric synthesis of the selective tricyclic inhibitor was also achieved using a chiral α-hydroxy ketone.

Original languageEnglish
Pages (from-to)1751-1770
Number of pages20
JournalBioorganic and Medicinal Chemistry
Volume19
Issue number5
DOIs
Publication statusPublished - Mar 1 2011

Fingerprint

Steroid 17-alpha-Hydroxylase
Structure-Activity Relationship
Derivatives
Cytochrome P-450 CYP3A
Human Activities
Pharmacokinetics
Ketones
Haplorhini
Rats

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

17,20-Lyase inhibitors. Part 4 : Design, synthesis and structure-activity relationships of naphthylmethylimidazole derivatives as novel 17,20-lyase inhibitors. / Kaku, Tomohiro; Matsunaga, Nobuyuki; Ojida, Akio; Tanaka, Toshimasa; Hara, Takahito; Yamaoka, Masuo; Kusaka, Masami; Tasaka, Akihiro.

In: Bioorganic and Medicinal Chemistry, Vol. 19, No. 5, 01.03.2011, p. 1751-1770.

Research output: Contribution to journalArticle

Kaku, Tomohiro ; Matsunaga, Nobuyuki ; Ojida, Akio ; Tanaka, Toshimasa ; Hara, Takahito ; Yamaoka, Masuo ; Kusaka, Masami ; Tasaka, Akihiro. / 17,20-Lyase inhibitors. Part 4 : Design, synthesis and structure-activity relationships of naphthylmethylimidazole derivatives as novel 17,20-lyase inhibitors. In: Bioorganic and Medicinal Chemistry. 2011 ; Vol. 19, No. 5. pp. 1751-1770.
@article{29ce94deae354339a5705243ee6ea28d,
title = "17,20-Lyase inhibitors. Part 4: Design, synthesis and structure-activity relationships of naphthylmethylimidazole derivatives as novel 17,20-lyase inhibitors",
abstract = "A novel series of naphthylmethylimidazole derivatives and related compounds have been investigated as selective 17,20-lyase inhibitors. Optimization of the substituent at the 6-position on the naphthalene ring was performed to yield a methylcarbamoyl derivative, which exhibited potent inhibitory activity against human 17,20-lyase and promising selectivity (>200-fold) for 17,20-lyase over CYP3A4. Further modifications of the methylcarbamoyl derivative led to the discovery of the corresponding tricyclic compound, which showed highly potent activity against human 17,20-lyase (IC 50 19 nM) and good selectivity (>1000-fold) for inhibition of 17,20-lyase over CYP3A4. Additional biological evaluation revealed that the tricyclic compound had potent in vivo efficacy in monkeys and favorable pharmacokinetic profiles when administered in rats. Asymmetric synthesis of the selective tricyclic inhibitor was also achieved using a chiral α-hydroxy ketone.",
author = "Tomohiro Kaku and Nobuyuki Matsunaga and Akio Ojida and Toshimasa Tanaka and Takahito Hara and Masuo Yamaoka and Masami Kusaka and Akihiro Tasaka",
year = "2011",
month = "3",
day = "1",
doi = "10.1016/j.bmc.2011.01.017",
language = "English",
volume = "19",
pages = "1751--1770",
journal = "Bioorganic and Medicinal Chemistry",
issn = "0968-0896",
publisher = "Elsevier Limited",
number = "5",

}

TY - JOUR

T1 - 17,20-Lyase inhibitors. Part 4

T2 - Design, synthesis and structure-activity relationships of naphthylmethylimidazole derivatives as novel 17,20-lyase inhibitors

AU - Kaku, Tomohiro

AU - Matsunaga, Nobuyuki

AU - Ojida, Akio

AU - Tanaka, Toshimasa

AU - Hara, Takahito

AU - Yamaoka, Masuo

AU - Kusaka, Masami

AU - Tasaka, Akihiro

PY - 2011/3/1

Y1 - 2011/3/1

N2 - A novel series of naphthylmethylimidazole derivatives and related compounds have been investigated as selective 17,20-lyase inhibitors. Optimization of the substituent at the 6-position on the naphthalene ring was performed to yield a methylcarbamoyl derivative, which exhibited potent inhibitory activity against human 17,20-lyase and promising selectivity (>200-fold) for 17,20-lyase over CYP3A4. Further modifications of the methylcarbamoyl derivative led to the discovery of the corresponding tricyclic compound, which showed highly potent activity against human 17,20-lyase (IC 50 19 nM) and good selectivity (>1000-fold) for inhibition of 17,20-lyase over CYP3A4. Additional biological evaluation revealed that the tricyclic compound had potent in vivo efficacy in monkeys and favorable pharmacokinetic profiles when administered in rats. Asymmetric synthesis of the selective tricyclic inhibitor was also achieved using a chiral α-hydroxy ketone.

AB - A novel series of naphthylmethylimidazole derivatives and related compounds have been investigated as selective 17,20-lyase inhibitors. Optimization of the substituent at the 6-position on the naphthalene ring was performed to yield a methylcarbamoyl derivative, which exhibited potent inhibitory activity against human 17,20-lyase and promising selectivity (>200-fold) for 17,20-lyase over CYP3A4. Further modifications of the methylcarbamoyl derivative led to the discovery of the corresponding tricyclic compound, which showed highly potent activity against human 17,20-lyase (IC 50 19 nM) and good selectivity (>1000-fold) for inhibition of 17,20-lyase over CYP3A4. Additional biological evaluation revealed that the tricyclic compound had potent in vivo efficacy in monkeys and favorable pharmacokinetic profiles when administered in rats. Asymmetric synthesis of the selective tricyclic inhibitor was also achieved using a chiral α-hydroxy ketone.

UR - http://www.scopus.com/inward/record.url?scp=79952187333&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79952187333&partnerID=8YFLogxK

U2 - 10.1016/j.bmc.2011.01.017

DO - 10.1016/j.bmc.2011.01.017

M3 - Article

C2 - 21316976

AN - SCOPUS:79952187333

VL - 19

SP - 1751

EP - 1770

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

SN - 0968-0896

IS - 5

ER -