Design and synthesis of Rho kinase inhibitors (II)

Iwakubo, Masayuki; Takami, Akira; Okada, Yuji; Kawata, Takehisa; Tagami, Yoshimichi; Ôhashi, Hiroshi; Sato, Motoko; Sugiyama, Terumi; Fukushima, Kayoko; Iijima, Hiroshi

doi:10.1016/j.bmc.2006.09.052

Cited by 52 publications

(32 citation statements)

References 60 publications

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“…The structures of ROCK II inhibitors (1-138, Tables A1 and A2 under supplementary material) were collected from recently published literature [7][8][9]. Despite that the collected inhibitors were gathered from three separate articles, they were bioassayed employing the same bioassay methodology.…”

Section: Data Setmentioning

confidence: 99%

“…The main focus of recent efforts towards the development of new ROCK II inhibitors concentrate on structurebased ligand design [7][8][9][10]. To date, several human ROCK II complexes have been resolved by X-ray crystallography and solution NMR, e.g., PDB codes: 2H9V, 2ROW, 2ROV, 2F2U [11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

“…We employed the CATALYST-HYPOGEN module of the software package Discovery Studio [35] to construct plausible binding hypotheses for a diverse list of ROCKII inhibitors [7][8][9]. Subsequently, genetic function algorithm (GFA) and multiple linear regression (MLR) analyses were employed to search for an optimal QSAR that combine high-quality binding pharmacophores with other molecular descriptors capable of explaining bioactivity variation across a collection of diverse ROCK II inhibitors.…”

Section: Introductionmentioning

confidence: 99%

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Elaborate ligand-based modeling reveal new submicromolar Rho kinase inhibitors

Shahin

Alqtaishat

Taha

2011

J Comput Aided Mol Des

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Rho Kinase (ROCKII) has been recently implicated in several cardiovascular diseases prompting several attempts to discover and optimize new ROCKII inhibitors. Towards this end we explored the pharmacophoric space of 138 ROCKII inhibitors to identify high quality pharmacophores. The pharmacophoric models were subsequently allowed to compete within quantitative structure-activity relationship (QSAR) context. Genetic algorithm and multiple linear regression analysis were employed to select an optimal combination of pharmacophoric models and 2D physicochemical descriptors capable of accessing self-consistent QSAR of optimal predictive potential (r (77) = 0.84, F = 18.18, r (LOO) (2) = 0.639, r (PRESS) (2) against 19 external test inhibitors = 0.494). Two orthogonal pharmacophores emerged in the QSAR equation suggesting the existence of at least two binding modes accessible to ligands within ROCKII binding pocket. Receiver operating characteristic (ROC) curve analyses established the validity of QSAR-selected pharmacophores. Moreover, the successful pharmacophores models were found to be comparable with crystallographically resolved ROCKII binding pocket. We employed the pharmacophoric models and associated QSAR equation to screen the national cancer institute (NCI) list of compounds Eight submicromolar ROCKII inhibitors were identified. The most potent gave IC(50) values of 0.7 and 1.0 μM.

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Section: Data Setmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Elaborate ligand-based modeling reveal new submicromolar Rho kinase inhibitors

Shahin

Alqtaishat

Taha

2011

J Comput Aided Mol Des

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“…The Structure Activity Relationship (SAR) studies of 1H-indazole analogs (45) by Iwakubo et al (2007) indicated that the cell-free enzyme inhibitory potential of Rho kinase inhibitors having the 1H-indazole scaffold did not necessarily correlate with their inhibitory potential toward the chemotaxis of cultured cells.…”

Section: Indazoles As Antihypertensive Agentsmentioning

confidence: 99%

Indazole: a medicinally important heterocyclic moiety

et al. 2011

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This article reveals the various biological activities of the heterocyclic compound, indazole, including anti-inflammatory, antimicrobial, antiHIV, anticancer, hypoglycemic, antiprotozoal, antihypertensive, and other activities. From the observed biological activities of the indazole moiety, it is concluded that the medicinal properties of indazole have to be explored in the near future for the treatment of various pathological conditions.

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“…[1][2][3][4][5][6] Many synthetic indazoles, however, are known and recognized by their pharmaceutical activity, which has inspired the development of a number of new syntheses for the indazole ring system. [7][8][9][10] Certain indazoles act as dopamine D2 receptor antagonists, [11][12][13] antipyretic and anti-inflammatory agents (bendazac and benzidamine), [14] analgesics [15,16] or anti-HIV protease [17,18] and Rho kinase inhibitors [19,20] and are used in the treatment of diabetes [7,21,22] and obesity. [23] Other derivatives exhibit antitumour (combretastatin), [24][25][26][27][28] CNS (granisetron), [8] bronchodilatory, vasodilatory or neuroprotectant activities.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of New 1H‐Indazoles through Diels–Alder Transformations of 4‐Styrylpyrazoles under Microwave Irradiation Conditions

Silva

Pinto

et al. 2009

Eur J Org Chem

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Microwave irradiation under solvent-free conditions induces 1-acetyl-4-styrylpyrazoles to undergo Diels-Alder cycloaddition reactions with N-methyl-or N-phenylmaleimide to give tetrahydroindazoles in good yields and with high selectivities. With conventional heating, these reactions either do not occur or afford only traces of the cycloadducts. These cycloadducts were then converted into the corresponding 1H-

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Design and synthesis of Rho kinase inhibitors (II)

Cited by 52 publications

References 60 publications

Elaborate ligand-based modeling reveal new submicromolar Rho kinase inhibitors

Elaborate ligand-based modeling reveal new submicromolar Rho kinase inhibitors

Indazole: a medicinally important heterocyclic moiety

Synthesis of New 1H‐Indazoles through Diels–Alder Transformations of 4‐Styrylpyrazoles under Microwave Irradiation Conditions

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