Tricyclic pharmacophore-based molecules as novel integrin αvβ3 antagonists. Part III: Synthesis of potent antagonists with αvβ3/α IIbβ3 dual activity and improved water solubility

Minoru Ishikawa; Yukiko Hiraiwa; Dai Kubota; Masaki Tsushima; Takashi Watanabe; Shoichi Murakami; Shokichi Ouchi; Keiichi Ajito

doi:10.1016/j.bmc.2005.10.055

Tricyclic pharmacophore-based molecules as novel integrin α_vβ₃ antagonists. Part III: Synthesis of potent antagonists with α_vβ₃/α _IIbβ₃ dual activity and improved water solubility

Minoru Ishikawa, Yukiko Hiraiwa, Dai Kubota, Masaki Tsushima, Takashi Watanabe, Shoichi Murakami, Shokichi Ouchi, Keiichi Ajito

LIF - Molecular and Chemical Life Science

Meiji Holdings Co., Ltd.

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

42 Citations (Scopus)

Abstract

In order to optimize our novel integrin α_vβ ₃/α_IIbβ₃ dual antagonists, spatial screening at the N-terminus was performed. The α_vβ ₃ antagonistic activity varied depending on the space that was occupied by the N-terminus, but high potency against α_IIbβ ₃ was well maintained. The (3S)-aminopiperidine analogue had the strongest activity against α_vβ₃, and the S isomer at piperidine was more potent than the R isomer. Compounds selected on the basis of SAR analysis of a novel lead compound showed acceptable early absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles and sufficient water solubility for use as infusion drugs. Docking studies with the α_vβ₃ receptor were performed to confirm the SAR findings.

Original language	English
Pages (from-to)	2131-2150
Number of pages	20
Journal	Bioorganic and Medicinal Chemistry
Volume	14
Issue number	7
DOIs	https://doi.org/10.1016/j.bmc.2005.10.055
Publication status	Published - 2006 Apr 1

Keywords

3-aminopiperidine derivatives
Acute ischemic disease
Integrin αβ antagonist
Integrin αβ antagonist

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10.1016/j.bmc.2005.10.055

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Ishikawa, M., Hiraiwa, Y., Kubota, D., Tsushima, M., Watanabe, T., Murakami, S., Ouchi, S., & Ajito, K. (2006). Tricyclic pharmacophore-based molecules as novel integrin α_vβ₃ antagonists. Part III: Synthesis of potent antagonists with α_vβ₃/α _IIbβ₃ dual activity and improved water solubility. Bioorganic and Medicinal Chemistry, 14(7), 2131-2150. https://doi.org/10.1016/j.bmc.2005.10.055

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title = "Tricyclic pharmacophore-based molecules as novel integrin αvβ3 antagonists. Part III: Synthesis of potent antagonists with αvβ3/α IIbβ3 dual activity and improved water solubility",

abstract = "In order to optimize our novel integrin αvβ 3/αIIbβ3 dual antagonists, spatial screening at the N-terminus was performed. The αvβ 3 antagonistic activity varied depending on the space that was occupied by the N-terminus, but high potency against αIIbβ 3 was well maintained. The (3S)-aminopiperidine analogue had the strongest activity against αvβ3, and the S isomer at piperidine was more potent than the R isomer. Compounds selected on the basis of SAR analysis of a novel lead compound showed acceptable early absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles and sufficient water solubility for use as infusion drugs. Docking studies with the αvβ3 receptor were performed to confirm the SAR findings.",

keywords = "3-aminopiperidine derivatives, Acute ischemic disease, Integrin αβ antagonist, Integrin αβ antagonist",

author = "Minoru Ishikawa and Yukiko Hiraiwa and Dai Kubota and Masaki Tsushima and Takashi Watanabe and Shoichi Murakami and Shokichi Ouchi and Keiichi Ajito",

year = "2006",

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language = "English",

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Ishikawa, M, Hiraiwa, Y, Kubota, D, Tsushima, M, Watanabe, T, Murakami, S, Ouchi, S & Ajito, K 2006, 'Tricyclic pharmacophore-based molecules as novel integrin α_vβ₃ antagonists. Part III: Synthesis of potent antagonists with α_vβ₃/α _IIbβ₃ dual activity and improved water solubility', Bioorganic and Medicinal Chemistry, vol. 14, no. 7, pp. 2131-2150. https://doi.org/10.1016/j.bmc.2005.10.055

Tricyclic pharmacophore-based molecules as novel integrin α_vβ₃ antagonists. Part III: Synthesis of potent antagonists with α_vβ₃/α _IIbβ₃ dual activity and improved water solubility. / Ishikawa, Minoru; Hiraiwa, Yukiko; Kubota, Dai et al.
In: Bioorganic and Medicinal Chemistry, Vol. 14, No. 7, 01.04.2006, p. 2131-2150.

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

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T1 - Tricyclic pharmacophore-based molecules as novel integrin αvβ3 antagonists. Part III

T2 - Synthesis of potent antagonists with αvβ3/α IIbβ3 dual activity and improved water solubility

AU - Ishikawa, Minoru

AU - Hiraiwa, Yukiko

AU - Kubota, Dai

AU - Tsushima, Masaki

AU - Watanabe, Takashi

AU - Murakami, Shoichi

AU - Ouchi, Shokichi

AU - Ajito, Keiichi

PY - 2006/4/1

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KW - 3-aminopiperidine derivatives

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KW - Integrin αβ antagonist

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Tricyclic pharmacophore-based molecules as novel integrin α_vβ₃ antagonists. Part III: Synthesis of potent antagonists with α_vβ₃/α _IIbβ₃ dual activity and improved water solubility

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