Structure-based design of non-peptidic pyridone aldehydes as inhibitors of interleukin-1β converting enzyme.

Bioorganic and Medicinal Chemistry Letters

Volumn 7, Issue 17, 1997, Pages 2181-2186

  Golec, Julian M C ^b,c   Mullican, Michael D ^a   Murcko, Mark A ^a   Wilson, Keith P ^a   Kay, David P ^b,d   Jones, Stuart D ^b,f   Murdoch, Robert ^b,e   Bemis, Guy W ^a   Raybuck, Scott A ^a   Luong, Yu Ping ^a   Livingston, David J ^a  

^a VERTEX PHARMACEUTICALS   (United States)

^b Roussel Laboratories Ltd   (United Kingdom)

^c Cantab Pharmaceuticals Ltd   (United Kingdom)

^d BIOCOMPATIBLES UK LTD   (United Kingdom)

^e Receptor Research Ltd   (United Kingdom)

^f Proteus Molecular Design Ltd   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

INTERLEUKIN 1BETA CONVERTING ENZYME; INTERLEUKIN 1BETA CONVERTING ENZYME INHIBITOR; PYRIDONE DERIVATIVE;

ARTICLE; CONFORMATION; CRYSTAL STRUCTURE; DRUG DESIGN; DRUG SYNTHESIS; HYDROGEN BOND; STRUCTURE ACTIVITY RELATION; X RAY CRYSTALLOGRAPHY;

EID: 0030885248     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(97)00394-6     Document Type: Article

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25. 12, with unit cell dimensions a = b = 64.4 Å, and c = 162.7 Å. R-merge for the data was 8.9%, with I/sig(I) = 2.3 at 2.6 Å resolution. The structure was solved by difference Fourier techniques using coordinates for a previous structure (Brookhaven entry 1ICE) solved in the same space group. The structure was refined against 7219 reflections (F>1sF) in the 7.0-2.6 Å resolution shell (85% completeness) to a R-factor of 18.1%, with deviations from ideal bond lengths and angles of 0.011 Å and 2.9°, respectively. Model refinement was carried out using the XPLOR suite of programs [Bruenger, A. T. (1992) X-PLOR version 3.1 Manual (Yale University Press, New Haven, CO),
26. sym) of 8.1% on intensities and completeness of 89% to 2.7 Å. Data to 2.2 Å was included in the refinement, but the completeness in the shells beyond 2.7Å was limited to 40% due to anisotropy in the diffraction pattern. The structure was refined using X-PLOR to a R-factor of 20.2% versus 12597 reflections (F>1sF) between 7-2.2 Å, with deviations from ideal bond lengths and angles of 0.009 Å and 2.7°, respectively.
27. 3) δ 8.16 (1H, d, J = 7.7), 7.26 (5H, m), 7.03 (2H, d, J = 8.4), 6.61 (2H, d, J = 8.4), 6.03 (1H, d, J = 7.7), 4.58 (3H, m), 4.44 (1H, m), 4.13 (1H, m), 3.84 (2H, s), 3.07-2.30 (4H, m).
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