Design and synthesis of rho kinase inhibitors (III)

Masayuki Iwakubo; Atsuya Takami; Yuji Okada; Takehisa Kawata; Yoshimichi Tagami; Motoko Sato; Terumi Sugiyama; Kayoko Fukushima; Shinichiro Taya; Mutsuki Amano; Kozo Kaibuchi; Hiroshi Iijima

doi:10.1016/j.bmc.2006.10.028

Design and synthesis of rho kinase inhibitors (III)

Masayuki Iwakubo, Atsuya Takami, Yuji Okada, Takehisa Kawata, Yoshimichi Tagami, Motoko Sato, Terumi Sugiyama, Kayoko Fukushima, Shinichiro Taya, Mutsuki Amano, Kozo Kaibuchi, Hiroshi Iijima

Research output: Contribution to journal › Article › peer-review

46 Citations (Scopus)

Abstract

The structure-activity relationship of Rho kinase inhibitors bearing an isoquinoline scaffold was studied. N-(1-Benzyl-3-pyrrolidyl)-N-(5-isoquinolyl)amine analogues were optimized with respect to their inhibitory potencies for the enzyme and for chemotaxis. The potent analogues were further evaluated by an ex vivo test in which the selected compounds were orally administered to rats, and the Rho kinase inhibitory potency observed in the rat serum was evaluated 3 h after the administration. Compound 23g showed a high level of Rho kinase inhibitory activity in the rat serum and was stable in an in vitro metabolic test using a microsomal cytochrome preparation. The (R)-isomer of 23g displayed a higher level of inhibitory potency than the (S)-isomer in a cell-free kinase assay and in the cell migration assay (IC₅₀^ENZ = 25 nM and IC₅₀^MCP = 1 μ M). The (R)-isomer successfully inhibited the phosphorylation of MBS (myosin-binding subunit) in cells.

Original language	English
Pages (from-to)	1022-1033
Number of pages	12
Journal	Bioorganic and Medicinal Chemistry
Volume	15
Issue number	2
DOIs	https://doi.org/10.1016/j.bmc.2006.10.028
Publication status	Published - 15-01-2007
Externally published	Yes

All Science Journal Classification (ASJC) codes

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

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10.1016/j.bmc.2006.10.028

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title = "Design and synthesis of rho kinase inhibitors (III)",

abstract = "The structure-activity relationship of Rho kinase inhibitors bearing an isoquinoline scaffold was studied. N-(1-Benzyl-3-pyrrolidyl)-N-(5-isoquinolyl)amine analogues were optimized with respect to their inhibitory potencies for the enzyme and for chemotaxis. The potent analogues were further evaluated by an ex vivo test in which the selected compounds were orally administered to rats, and the Rho kinase inhibitory potency observed in the rat serum was evaluated 3 h after the administration. Compound 23g showed a high level of Rho kinase inhibitory activity in the rat serum and was stable in an in vitro metabolic test using a microsomal cytochrome preparation. The (R)-isomer of 23g displayed a higher level of inhibitory potency than the (S)-isomer in a cell-free kinase assay and in the cell migration assay (IC50ENZ = 25 nM and IC50MCP = 1 μ M). The (R)-isomer successfully inhibited the phosphorylation of MBS (myosin-binding subunit) in cells.",

author = "Masayuki Iwakubo and Atsuya Takami and Yuji Okada and Takehisa Kawata and Yoshimichi Tagami and Motoko Sato and Terumi Sugiyama and Kayoko Fukushima and Shinichiro Taya and Mutsuki Amano and Kozo Kaibuchi and Hiroshi Iijima",

note = "Funding Information: The authors wish to thank Ms. Takemi Tokieda for technical assistance, Mr. Kinya Kubo, Mr. Mitsunori Kanazawa, and Mr. Shinichi Ohyama for their advice and technical help in the microsome experiments. We also thank Dr. Kazuo Kubo and Dr. Elizabeth A Kamei for reading the manuscript. We are grateful to Dr. Takeshi Ohtani and Dr. Kazuta Takemura who contributed to the initiation of this project. This work was in part supported by the grant from the National Institute of Biomedical Innovation. ",

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T1 - Design and synthesis of rho kinase inhibitors (III)

AU - Iwakubo, Masayuki

AU - Takami, Atsuya

AU - Okada, Yuji

AU - Kawata, Takehisa

AU - Tagami, Yoshimichi

AU - Sato, Motoko

AU - Sugiyama, Terumi

AU - Fukushima, Kayoko

AU - Taya, Shinichiro

AU - Amano, Mutsuki

AU - Kaibuchi, Kozo

AU - Iijima, Hiroshi

N1 - Funding Information: The authors wish to thank Ms. Takemi Tokieda for technical assistance, Mr. Kinya Kubo, Mr. Mitsunori Kanazawa, and Mr. Shinichi Ohyama for their advice and technical help in the microsome experiments. We also thank Dr. Kazuo Kubo and Dr. Elizabeth A Kamei for reading the manuscript. We are grateful to Dr. Takeshi Ohtani and Dr. Kazuta Takemura who contributed to the initiation of this project. This work was in part supported by the grant from the National Institute of Biomedical Innovation.

PY - 2007/1/15

Y1 - 2007/1/15

N2 - The structure-activity relationship of Rho kinase inhibitors bearing an isoquinoline scaffold was studied. N-(1-Benzyl-3-pyrrolidyl)-N-(5-isoquinolyl)amine analogues were optimized with respect to their inhibitory potencies for the enzyme and for chemotaxis. The potent analogues were further evaluated by an ex vivo test in which the selected compounds were orally administered to rats, and the Rho kinase inhibitory potency observed in the rat serum was evaluated 3 h after the administration. Compound 23g showed a high level of Rho kinase inhibitory activity in the rat serum and was stable in an in vitro metabolic test using a microsomal cytochrome preparation. The (R)-isomer of 23g displayed a higher level of inhibitory potency than the (S)-isomer in a cell-free kinase assay and in the cell migration assay (IC50ENZ = 25 nM and IC50MCP = 1 μ M). The (R)-isomer successfully inhibited the phosphorylation of MBS (myosin-binding subunit) in cells.

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Design and synthesis of rho kinase inhibitors (III)

Abstract

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