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Volumn 12, Issue 21, 2004, Pages 5689-5710

Bicyclic peptidomimetic tetrahydrofuro[3,2-b]pyrrol-3-one and hexahydrofuro[3,2-b]pyridine-3-one based scaffolds: Synthesis and cysteinyl proteinase inhibition

Author keywords

Anti resorptive; Bicyclic ketones; Cysteinyl proteinase inhibition

Indexed keywords

CYSTEINE PROTEINASE; PYRIDINE DERIVATIVE;

EID: 4644351694     PISSN: 09680896     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmc.2004.07.054     Document Type: Article
Times cited : (54)

References (75)
  • 17
    • 4644263817 scopus 로고    scopus 로고
    • Patent WO 02/057270
    • See: (a) Quibell, M. Patent WO 02/057270
    • Quibell, M.1
  • 22
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    • G. Mann Z. Chem. 6 3 1966 106
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  • 30
    • 4644366675 scopus 로고    scopus 로고
    • No references are found for cis or trans-bicyclo[5.2.0]nonan-6-one although a CAS registry is present 105104-52-7
    • (c) No references are found for cis or trans-bicyclo[5.2.0]nonan-6-one although a CAS registry is present 105104-52-7
  • 31
    • 0000723778 scopus 로고
    • No references are found for trans-bicyclo[3.3.0]octan-2-one whilst the cis isomer is well known, for example, see: A.C. Cope, H.H. Lee, and H.E. Petree J. Am. Chem. Soc. 80 1958 2849
    • (1958) J. Am. Chem. Soc. , vol.80 , pp. 2849
    • Cope, A.C.1    Lee, H.H.2    Petree, H.E.3
  • 38
    • 4644369492 scopus 로고    scopus 로고
    • note
    • 2 ketone carbonyl, heteroatoms as appropriate, the enol intermediate and finally through si and re stereofacial addition of methanethiol as a model of the proteinase bound intermediate hemithioketal. Each compound was generated in ChemDraw Ultra (v6.0, CambridgeSoft Corp.), then copy and pasted into Chem3D Pro (v5.0, CambridgeSoft Corp.) for an MM2 energy minimisation (RMS gradient = 0.1). The 'total energy' was then calculated for each minimised conformer, which relates to the total steric energy of the conformation and hence the relative stability of the conformer
  • 39
    • 37049047848 scopus 로고
    • It cannot be assumed that the literature detailed relative stabilities for carbocycle and ketocarbocycles are conserved upon the introduction of the heteroatoms into ketoheterocycles 4-8. Indeed, literature shows that certain heterocyclic analogues of bicyclo[3.3.0]octane exist in both cis and trans-fused conformations exist, for example, see: L.N. Owen, and A.G. Peto J. Chem. Soc. 1955 2383
    • (1955) J. Chem. Soc. , pp. 2383
    • Owen, L.N.1    Peto, A.G.2
  • 40
    • 0034676308 scopus 로고    scopus 로고
    • A clear example of the point made in Ref. 16 is shown by the stable 5,5-bicycle detailed by GSK that is trans-fused and provides a generalised scaffold for serine protease inhibition. However, this scaffold does not contain a ketone functionality β to either bridgehead position and as such does not have a facile mechanism for loss of chirality through enolisation. See: A.D. Borthwick, S.J. Angier, A.J. Crame, A.M. Exall, T.M. Haley, G.J. Hart, A.M. Mason, A.M.K. Pennell, and G.G. Weingarten J. Med. Chem. 43 2000 4452
    • (2000) J. Med. Chem. , vol.43 , pp. 4452
    • Borthwick, A.D.1    Angier, S.J.2    Crame, A.J.3    Exall, A.M.4    Haley, T.M.5    Hart, G.J.6    Mason, A.M.7    Pennell, A.M.K.8    Weingarten, G.G.9
  • 48
    • 4644368989 scopus 로고    scopus 로고
    • note
    • A further example of the deleterious effects of P1 inhibitor secondary amide N-methylation is provided in Ref. 19. However, here only a fourfold loss in potency was observed, but this effect is detailed in a symmetrical inhibitor, which may potentially bind is a reverse manner, placing the N-methylated residue in an alternative proteinase binding pocket
  • 49
    • 4644358769 scopus 로고    scopus 로고
    • note
    • For example see PDB codes, cathepsin K 1au0 (cis), 1au2 (cis), 1bgo (trans), 1mem (trans), 1nl6 (cis), 1nj7 (cis); cathepsin S 1ms6 (cis), 1npz (cis); cathepsin V 1fh0 (trans); cruzain 1aim (cis)
  • 50
    • 84862428534 scopus 로고    scopus 로고
    • note
    • 25 was built to examine the products of both re and si stereofacial addition of the thiolate. As part of the assessment, calculations were performed on the isolated hemithioketal tetrahedral intermediate extracted from the predicted bound complex, to ascertain whether the binding model contained a reasonable energy inhibitor conformation. Conformer energy calculations were performed using CAChe (Conflex molecular mechanics engine, CAChe Group, Fujitsu). Additionally, the full modelling process considering each possible binding orientation was repeated using the literature cruzain X-ray structure 1aim and the mammalian cathepsin S X-ray structure 1ms6. Virtually identical conclusions concerning the preferred binding orientations described herein for the cathepsin K 1mem and 1au0 structures were found when substituting with the 1aim and 1ms6 structures
  • 51
    • 4644366676 scopus 로고    scopus 로고
    • note
    • Predictions of likely binding conformations were performed as previously described (Ref. 5) and based solely upon comparison of the four possible re/si/prime side/nonprime side complexes for each bicycle. Major considerations in the development of a ranking for each possibility were the identification of a reasonable energy conformer for the inhibitor that retained a good hydrogen bonding network to the proteinase along with the absence of spatial clashes. The overall goodness of fit was assessed using the scoring functions generated by the software package 'GOLD 2.1' (Cambridge Crystallographic Data Centre) performing the calculations on the tetrahedral intermediates
  • 55
    • 4644368134 scopus 로고    scopus 로고
    • note
    • 26 (trans giving C-2 at 67.7/67.9 and C-3 at 74.0/75.1 ppm; cis giving C-2 at 63.3/64.0 and C-3 at 71.3/72.0 ppm)
  • 57
    • 0345550452 scopus 로고    scopus 로고
    • For a general synthesis of Fmoc-aminoacid chloromethylketones from the corresponding diazomethylketones, see: J.L. Wood, L. Huang, and J.A. Ellman J. Comb. Chem. 5 2003 869
    • (2003) J. Comb. Chem. , vol.5 , pp. 869
    • Wood, J.L.1    Huang, L.2    Ellman, J.A.3
  • 60
    • 4644349206 scopus 로고    scopus 로고
    • note
    • 3). Compounds (-)39, (-)40, 41 and (+)42 are enantiomers of the fully detailed compounds (+)33, (+)34, 35 and (-)13 and exhibited virtually identical NMR spectra to those annotated herein. Preparation of (-)39, (-)40, 41 and (+)42 are unpublished syntheses, although see Ref. a for preliminary disclosure
  • 63
    • 4644368564 scopus 로고    scopus 로고
    • note
    • 2-COOH could be observed in most crude examples. This side-product, that derives from cleavage of the 3°amide bond, was readily removed by semi-preparative HPLC
  • 64
    • 4644369877 scopus 로고    scopus 로고
    • note
    • 2-COOH product was the major mechanism of compound instability when assessed under acid, neutral and basic buffered conditions
  • 65
    • 4644267191 scopus 로고    scopus 로고
    • Patent WO 00/69855
    • Monocyclic analogues such as 49a,b were prepared for comparison following the general methods detailed in Quibell, M.; Taylor, S. Patent WO 00/69855
    • Quibell, M.1    Taylor, S.2
  • 66
    • 4644349207 scopus 로고    scopus 로고
    • note
    • We are unable to further rationalise such a clear experimental result using the simple design tools and techniques described herein (Refs. 22,23)
  • 68
    • 4644374183 scopus 로고    scopus 로고
    • note
    • 6b,6c due to the earlier described broad elution profile and our failure to prepare the authentic trans standard for comparison. However, all our evidence, build upon the assumption that the cis and trans-fused diastereoisomers would show different and separable physical properties, gave no evidence for loss of β-chirality. For example, analogue 10 was prepared by the solid phase methods described herein on a 50 μM scale and purified by standard silica chromatography. TLC analysis of purified 10 exhibited a single tight UV positive spot that remained unchanged after three days in a range of organic and mixed organic/aqueous buffers. Additionally, NMR analysis of analogue 10 showed no evidence for the trans 5,5-bicycle even upon prolonged dissolution in NMR solvents. Broadly similar finding were evident for the corresponding 6,5-bicycle analogue 11


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