<i>N</i>-Arylpiperazinone Inhibitors of Farnesyltransferase:  Discovery and Biological Activity

Tm, Williams; Jm, Bergman; Brashear, Karen M.; Mj, Breslin; Cj, Dinsmore; Jh, Hutchinson; Sc, MacTough; Ca, Stump; Dd, Wei; Cb, Zartman; Mj, Bogusky; Jc, Culberson; Buser-Doepner, Carolyn; Davide, Joseph P.; Ib, Greenberg; Hamilton, Katherine; Ks, Koblan; Ne, Kohl; D, Liu; Rb, Lobell; Sd, Mosser; Tj, O'Neill; Rands, Elaine; Schaber,; Huff,

doi:10.1021/jm990254z

Cited by 50 publications

(32 citation statements)

References 28 publications

(32 reference statements)

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“…(iv) 4-[[( tert -Butyldimethylsilyl)oxy]methyl]-1-(triphenylmethyl)imidazole (33). 4-(Hydroxymethyl)-1-(triphenylmethyl)imidazole ( 32 ) (1.97 g, 5.72 mmol) and 4-(dimethylamino)pyridine (280 mg, 2.29 mmol) were stirred in CH 2 Cl 2 (15 mL), and tert -butyldimethylsilyl chloride (905 mg, 6.01 mmol) was added. After 1 min, triethylamine (0.88 mL, 6.31 mmol) was added dropwise over 3 min.…”

Section: Methodsmentioning

confidence: 99%

3-Aminopyrrolidinone Farnesyltransferase Inhibitors: Design of Macrocyclic Compounds with Improved Pharmacokinetics and Excellent Cell Potency

et al. 2002

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A series of macrocyclic 3-aminopyrrolidinone farnesyltransferase inhibitors (FTIs) has been synthesized. Compared with previously described linear 3-aminopyrrolidinone FTIs such as compound 1, macrocycles such as 49 combined improved pharmacokinetic properties with a reduced potential for side effects. In dogs, oral bioavailability was good to excellent, and increases in plasma half-life were due to attenuated clearance. It was observed that in vivo clearance correlated with the flexibility of the molecules and this concept proved useful in the design of FTIs that exhibited low clearance, such as FTI 78. X-ray crystal structures of compounds 49 and 66 complexed with farnesyltransferase (FTase)-farnesyl diphosphate (FPP) were determined, and they provide details of the key interactions in such ternary complexes. Optimization of this 3-aminopyrrolidinone series of compounds led to significant increases in potency, providing 83 and 85, the most potent inhibitors of FTase in cells described to date.

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Section: Methodsmentioning

confidence: 99%

3-Aminopyrrolidinone Farnesyltransferase Inhibitors: Design of Macrocyclic Compounds with Improved Pharmacokinetics and Excellent Cell Potency

et al. 2002

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“…This reaction allowed for the rapid access to piperazinones with high stereoselectivity (Scheme ). In this process, the homochiral aziridine aldehyde dimer participates in iminium ion formation with an amino acid, followed by stereoselectivity-determining isocyanide addition . Finally, the aziridine attacks the carbonyl group of the mixed anhydride, directing the reaction toward piperazinone formation …”

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Synthesis of Chiral Piperazinones Using Amphoteric Aziridine Aldehyde Dimers and Functionalized Isocyanides

et al. 2016

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We have evaluated a range of functionalized isocyanides in the aziridine aldehyde-driven multicomponent synthesis of piperazinones. High diasteroselectivity for each isocyanide was observed. A theoretical evaluation of the reaction course corroborates the experimental data. Moreover, the reactivity of cis- and trans-configured aziridine aldehyde dimers has been compared. This study further probes the dimer-driven mechanism of cyclization and enables an efficient access to a wide range of chiral piperazinones bearing functionalized side chains.

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“…Numerous biologically interesting natural products and medicinally important small molecules contain 1,3-azoles (e.g., imidazole, benzimidazole, imidazopyridine, and purine) (Figure ). One challenge for the synthesis of 1,3-azole-containing molecules is the ambident nature of the azole toward N -alkylation chemistry . A particularly challenging situation arises when the more sterically hindered nitrogen of the unsymmetrical azole is the target for alkylation.…”

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Direct, Regioselective N-Alkylation of 1,3-Azoles

2015

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N-Arylpiperazinone Inhibitors of Farnesyltransferase: Discovery and Biological Activity

Cited by 50 publications

References 28 publications

3-Aminopyrrolidinone Farnesyltransferase Inhibitors: Design of Macrocyclic Compounds with Improved Pharmacokinetics and Excellent Cell Potency

3-Aminopyrrolidinone Farnesyltransferase Inhibitors: Design of Macrocyclic Compounds with Improved Pharmacokinetics and Excellent Cell Potency

Synthesis of Chiral Piperazinones Using Amphoteric Aziridine Aldehyde Dimers and Functionalized Isocyanides

Direct, Regioselective N-Alkylation of 1,3-Azoles

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