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3-Aminopyrrolidinone farnesyltransferase inhibitors: design of macrocyclic compounds with improved pharmacokinetics and excellent cell potency.

Bell IM, Gallicchio SN, Abrams M, Beese LS, Beshore DC, Bhimnathwala H, Bogusky MJ, Buser CA, Culberson JC, Davide J, Ellis-Hutchings M, Fernandes C, Gibbs JB, Graham SL, Hamilton KA, Hartman GD, Heimbrook DC, Homnick CF, Huber HE, Huff JR, Kassahun K, Koblan KS, Kohl NE, Lobell RB, Lynch JJ, Robinson R, Rodrigues AD, Taylor JS, Walsh ES, Williams TM, Zartman CB
J Med Chem 45 2388-409 (2002)
Cited: 40 times
EuropePMC logo PMID: 12036349

Abstract

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.

Articles - 1ld8 mentioned but not cited (5)

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Reviews citing this publication (5)

  1. The exploration of macrocycles for drug discovery--an underexploited structural class. Driggers EM, Hale SP, Lee J, Terrett NK. Nat Rev Drug Discov 7 608-624 (2008)
  2. Thematic review series: lipid posttranslational modifications. Structural biology of protein farnesyltransferase and geranylgeranyltransferase type I. Lane KT, Beese LS. J Lipid Res 47 681-699 (2006)
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  5. Inhibition of farnesyltransferase: a rational approach to treat cancer? Puntambekar DS, Giridhar R, Yadav MR. J Enzyme Inhib Med Chem 22 127-140 (2007)

Articles citing this publication (30)

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  3. A fluorine scan of the phenylamidinium needle of tricyclic thrombin inhibitors: effects of fluorine substitution on pKa and binding affinity and evidence for intermolecular C-F...CN interactions. Olsen J, Seiler P, Wagner B, Fischer H, Tschopp T, Obst-Sander U, Banner DW, Kansy M, Müller K, Diederich F. Org Biomol Chem 2 1339-1352 (2004)
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  7. Structural analysis of DNA-PKcs: modelling of the repeat units and insights into the detailed molecular architecture. Brewerton SC, Doré AS, Drake AC, Leuther KK, Blundell TL. J Struct Biol 145 295-306 (2004)
  8. A new class of non-thiazolidinedione, non-carboxylic-acid-based highly selective peroxisome proliferator-activated receptor (PPAR) γ agonists: design and synthesis of benzylpyrazole acylsulfonamides. Rikimaru K, Wakabayashi T, Abe H, Imoto H, Maekawa T, Ujikawa O, Murase K, Matsuo T, Matsumoto M, Nomura C, Tsuge H, Arimura N, Kawakami K, Sakamoto J, Funami M, Mol CD, Snell GP, Bragstad KA, Sang BC, Dougan DR, Tanaka T, Katayama N, Horiguchi Y, Momose Y. Bioorg Med Chem 20 714-733 (2012)
  9. Structural basis for binding and selectivity of antimalarial and anticancer ethylenediamine inhibitors to protein farnesyltransferase. Hast MA, Fletcher S, Cummings CG, Pusateri EE, Blaskovich MA, Rivas K, Gelb MH, Van Voorhis WC, Sebti SM, Hamilton AD, Beese LS. Chem Biol 16 181-192 (2009)
  10. Role of protein farnesylation events in the ABA-mediated regulation of the Pinoresinol-Lariciresinol Reductase 1 (LuPLR1) gene expression and lignan biosynthesis in flax (Linum usitatissimum L.). Corbin C, Decourtil C, Marosevic D, Bailly M, Lopez T, Renouard S, Doussot J, Dutilleul C, Auguin D, Giglioli-Guivarc'h N, Lainé E, Lamblin F, Hano C. Plant Physiol Biochem 72 96-111 (2013)
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  12. Stereoselective Inhibition of the hERG1 Potassium Channel. Grilo LS, Carrupt PA, Abriel H. Front Pharmacol 1 137 (2010)
  13. Computational Macrocyclization: From de novo Macrocycle Generation to Binding Affinity Estimation. Wagner V, Jantz L, Briem H, Sommer K, Rarey M, Christ CD. ChemMedChem 12 1866-1872 (2017)
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  15. Synthesis of N,N'-disubstituted 3-aminobenzo[c] and [d]azepin-2-ones as potent and specific farnesyl transferase inhibitors. Le Diguarher T, Ortuno JC, Shanks D, Guilbaud N, Pierré A, Raimbaud E, Fauchère JL, Hickman JA, Tucker GC, Casara PJ. Bioorg Med Chem Lett 14 767-771 (2004)
  16. Macrocycle Cell Permeability Measured by Solvation Free Energies in Polar and Apolar Environments. Kamenik AS, Kraml J, Hofer F, Waibl F, Quoika PK, Kahler U, Schauperl M, Liedl KR. J Chem Inf Model 60 3508-3517 (2020)
  17. Peptide chemistry applied to a new family of phenothiazine-containing inhibitors of human farnesyltransferase. Dumitriu GM, Ghinet A, Bîcu E, Rigo B, Dubois J, Farce A, Belei D. Bioorg Med Chem Lett 24 3180-3185 (2014)
  18. Solid-phase synthesis and pharmacological evaluation of a library of peptidomimetics as potential farnesyltransferase inhibitors: an approach to new lead compounds. Gilleron P, Millet R, Houssin R, Wlodarczyk N, Farce A, Lemoine A, Goossens JF, Chavatte P, Pommery N, Hénichart JP. Eur J Med Chem 41 745-755 (2006)
  19. Conformational analysis of macrocycles: comparing general and specialized methods. Olanders G, Alogheli H, Brandt P, Karlén A. J Comput Aided Mol Des 34 231-252 (2020)
  20. From pure FPP to mixed FPP and CAAX competitive inhibitors of farnesyl protein transferase. Lannuzel M, Lamothe M, Schambel P, Etiévant C, Hill B, Perez M. Bioorg Med Chem Lett 13 1459-1462 (2003)
  21. Synthesis and evaluation of a novel series of farnesyl protein transferase inhibitors as non-peptidic CAAX tetrapeptide analogues. Perez M, Maraval C, Dumond S, Lamothe M, Schambel P, Etiévant C, Hill B. Bioorg Med Chem Lett 13 1455-1458 (2003)
  22. Gene expression analysis in response to osmotic stimuli in the intervertebral disc with DNA microarray. Zhang W, Li X, Shang X, Zhao Q, Hu Y, Xu X, He R, Duan L, Zhang F. Eur J Med Res 18 62 (2013)
  23. Synthesis and primary cytotoxicity evaluation of arylmethylenenaphthofuranones derivatives. Lardic M, Patry C, Duflos M, Guillon J, Massip S, Cruzalegui F, Edmonds T, Giraudet S, Marini L, Leonce S. J Enzyme Inhib Med Chem 21 313-325 (2006)
  24. A cell-based radioligand binding assay for farnesyl: protein transferase inhibitors. Lobell RB, Davide JP, Kohl NE, Burns HD, Eng WS, Gibson RE. J Biomol Screen 8 430-438 (2003)
  25. Benchmark of Generic Shapes for Macrocycles. Reyes Romero A, Ruiz-Moreno AJ, Groves MR, Velasco-Velázquez M, Dömling A. J Chem Inf Model 60 6298-6313 (2020)
  26. Cyclization and Docking Protocol for Cyclic Peptide-Protein Modeling Using HADDOCK2.4. Charitou V, van Keulen SC, Bonvin AMJJ. J Chem Theory Comput 18 4027-4040 (2022)
  27. High-Quality Conformer Generation with CONFORGE: Algorithm and Performance Assessment. Seidel T, Permann C, Wieder O, Kohlbacher SM, Langer T. J Chem Inf Model 63 5549-5570 (2023)
  28. Incorporation of Perillyl Alcohol into Lipid-Based Nanocarriers Enhances the Antiproliferative Activity in Malignant Glioma Cells. Ahmed TA, Almehmady AM, Alharbi WS, Alshehri AA, Almughem FA, Altamimi RM, Alshabibi MA, Omar AM, El-Say KM. Biomedicines 11 2771 (2023)
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  30. Phenothiazine- and Carbazole-Cyanochalcones as Dual Inhibitors of Tubulin Polymerization and Human Farnesyltransferase. Zubaș A, Ghinet A, Farce A, Dubois J, Bîcu E. Pharmaceuticals (Basel) 16 888 (2023)


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