Discovery of potent imidazole and cyanophenyl containing farnesyltransferase inhibitors with improved oral bioavailability

Tong, Yunsong; Lin, Nan‐Horng; Wang, Le; Hasvold, Lisa; Wang, Weibo; Leonard, Nicholas M.; Li, Tongmei; Li, Qun; Cohen, Jerry D.; Gu, Wen-Zhen; Zhang, Haiying; Stoll, V.S.; Bauch, Joy; Marsh, Kennan C.; Rosenberg, Saul H.; Sham, Hing L.

doi:10.1016/s0960-894x(03)00195-1

Cited by 26 publications

(21 citation statements)

References 13 publications

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“…In an effort to optimize compounds (52) Tong and coworkers [45] synthesized four series of imidazole-bearing FTIs with nitrogen inserted into one of the cyanophenyl moieties (general structure (54)(55)(56)(57)). Most of the inhibitors show IC 50 values against FTase of less than 1 nM and cellular Ras processing EC 50 values of less than 10 nM.…”

Section: Imidazole Containing Inhibitors Of Protein Farnesyltransferasementioning

confidence: 99%

Author Index to Volume 12

2006

curr med chem

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Imidazoles are an important class of heterocycles and include many substances of both biological and chemical interest. They are part of a large number of highly significant biomolecules such as the essential amino acid histidine and related compounds, biotin, and the imidazole alkaloids. Insertion of the imidazole nucleus is an important synthetic strategy in drug discovery. Imidazole drugs have broad applications in many areas of clinical medicine. The imidazoles are a class of antifungal azole derivatives and have a broad spectrum of activities both in vitro and in vivo. The imidazole moiety is also contained in many histaminergic ligands for histamine H1, H2, and H3 receptors. These are currently used as tools in pharmacological studies. The important therapeutic properties of imidazole related drugs have encouraged the medicinal chemists to synthesize and test a large number of novel molecules. Some of these have chemotherapeutic properties, such as for example several FTase inhibitors with an imidazole moiety. Imidazole derivatives have also been shown to have antibacterial activity and recently several P38 MAP Kinase inhibitors and 5-Lipoxygenase inhibitors containing the imidazole moiety have been synthesized. This review reports current progress in the area of new biologically active imidazoles and recently discovered naturally occurring imidazole.

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Section: Imidazole Containing Inhibitors Of Protein Farnesyltransferasementioning

confidence: 99%

Author Index to Volume 12

2006

curr med chem

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“…We consider three protein halobenzene binding sites recently unraveled by high‐resolution X‐ray diffraction. These are farnesyl transferase (Ftase), coagulation FXa (factor Xa), and the HIV‐1 integrase (INT) . Such structures show that the halobenzene can reside in the neighborhood of electron‐rich as well as of electron‐deficient sites of the receptor.…”

Section: Introductionmentioning

confidence: 99%

Could the “Janus‐like” properties of the halobenzene CX bond (XCl, Br) be leveraged to enhance molecular recognition?

et al. 2014

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The CX bond in halobenzenes (XCl, Br) exhibits a dual character, being electron-deficient along the CX direction, and electron-rich on its flanks. We sought to amplify both features by resorting to electron-withdrawing and electron-donating substituents, respectively. This was done by quantum chemistry (QC) computations in the recognition sites of three protein targets: farnesyl transferase, coagulation factor Xa, and the HIV-1 integrase. In this context, some substituents, notably fluorine, CF3 , and NHCH3 , afforded significant overall gains in the binding energies as compared to the parent halobenzene, in the 2-5 kcal/mol range. In fact, we found that some di- and up to tetra-substitutions enabled even larger gains than those they contribute separately owing to many-body effects. Moreover, desolvation was also found to be a key contributor to the energy balances. As a consequence, some particular substituents, contributing to reduce the halobenzene dipole moment, accordingly reduced solvation: this factor acted in synergy with their enhancement of the intermolecular interaction energies along and around the CX bond. We could thus leverage the "Janus-like" properties of such a bond and the fact that it can be tuned and possibly amplified by well-chosen substituents. We propose a simple yet rigorous computational strategy resorting to QC to prescreen novel substituted halobenzenes. The QC results on the recognition sites then set benchmarks to validate polarizable molecular mechanics/dynamics approaches used to handle the entirety of the inhibitor-protein complex.

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“…Data set Table 1 shows the structures of the 192 compounds used in this study and their observed activities (pIC 50 ) [20][21][22][25][26][27][28]. The set is composed of 54 pyridones, 55 pyridylcontaining methyl ethers and 83 biphenyl methyl ethers.…”

Section: Methodsmentioning

confidence: 99%

“…Mainly based on structural modification of tipifarnib (Scheme 1), one of the most potent and selective non-thiol FT inhibitors in clinical trials, Abbott initiated a highly diverse series of imidazole-containing FT inhibitors through deletion of ring B and transposition of ring D [20][21][22][23][24][25][26][27][28]. In this work we studied 192 of the Abbott compounds and their FT inhibitory activities (IC 50 ) using CoMFA [29], CoMSIA [30] and docking [31] in order to gain understanding of the interaction between this series of compounds and FT.…”

Section: Introductionmentioning

confidence: 99%

Imidazole-containing farnesyltransferase inhibitors: 3D quantitative structure–activity relationships and molecular docking

Xie

Odde

Sivaprakasam

et al. 2009

J Comput Aided Mol Des

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One of the most promising anticancer and recent antimalarial targets is the heterodimeric zinc-containing protein farnesyltransferase (FT). In this work, we studied a highly diverse series of 192 Abbott-initiated imidazole-containing compounds and their FT inhibitory activities using 3D-QSAR and docking, in order to gain understanding of the interaction of these inhibitors with FT to aid development of a rational strategy for further lead optimization. We report several highly significant and predictive CoMFA and CoMSIA models. The best model, composed of CoMFA steric and electrostatic fields combined with CoMSIA hydrophobic and H-bond acceptor fields, had r (2) = 0.878, q (2) = 0.630, and r (pred) (2) = 0.614. Docking studies on the statistical outliers revealed that some of them had a different binding mode in the FT active site based on steric bulk and available active site space, explaining why the predicted activities differed from the experimental activities.

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Discovery of potent imidazole and cyanophenyl containing farnesyltransferase inhibitors with improved oral bioavailability

Cited by 26 publications

References 13 publications

Author Index to Volume 12

Author Index to Volume 12

Could the “Janus‐like” properties of the halobenzene CX bond (XCl, Br) be leveraged to enhance molecular recognition?

Imidazole-containing farnesyltransferase inhibitors: 3D quantitative structure–activity relationships and molecular docking

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