Nanomolar inhibitors for two distinct biological target families from a single synthetic sequence: A next step in combinatorial library design?

Angewandte Chemie - International Edition

Volumn 37, Issue 20, 1998, Pages 2848-2850

  Burns, Christopher J ^a   Groneberg, Robert D ^a   Salvino, Joseph M ^a   McGeehan, Gerard ^a   Condon, Stephen M ^a   Morris, Robert ^a   Morrissette, Matthew ^a   Mathew, Rose ^a   Darnbrough, Shelley ^a   Neuenschwander, Kent ^a   Scotese, Anthony ^a   Djuric, Stevan W ^a   Ullrich, John ^a   Labaudiniere, Richard ^a  

^a SANOFI   (France)

Author keywords

Combinatorial chemistry; Drug design; Enzyme inhibitors; Metalloenzymes; Phosphodiesterases

Indexed keywords

COLLAGENASE 1; GUANINE NUCLEOTIDE BINDING PROTEIN; MATRIX METALLOPROTEINASE; UNCLASSIFIED DRUG;

ARTICLE; CHEMICAL BINDING; ENZYME INHIBITION; MOLECULAR RECOGNITION; SEQUENCE ANALYSIS; STRUCTURE ACTIVITY RELATION; STRUCTURE ANALYSIS;

EID: 0032476829     PISSN: 14337851     EISSN: None     Source Type: Journal    
DOI: 10.1002/(sici)1521-3773(19981102)37:20<2848::aid-anie2848>3.3.co;2-3     Document Type: Article

References (29)

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23. 2SPh).
24. For our first libraries, almost 300 compounds (more than 200 from method B) were prepared and screened as singles using these routes (see ref. [14]). In general, yields from method A were greater than 30% overall, with an average yield of more than 80% for each step. For method B, overall yields were typically 5-25% (see the supporting information).
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27. 50 < 100nM in the PDE4 assay.
28. Consider, for example, compounds based on the 1,4-benzodiazepine (BZD) scaffold, which are rigid β-turn peptide mimics with known biopharmaceutical pedigree. Such features, combined with the plausibility of introducing three to four points of diversity onto the scaffold during its construction, have made BZD an appealing substructure for combinatorial library synthesis (for reviews, see S. H. DeWitt, A. W. Czarnik, Acc. Chem. Res. 1996, 29, 114-122
29. and J. A. Ellman, Acc. Chem. Res. 1996, 29, 132-143) and a prolific source of hits and leads against targets ranging across a number of biological target classes (CCK-A, FΓase, gpIIb/IIIa, etc.). In such cases, the desired end - hits and leads against multiple target families using a single synthetic route (or at least similar synthetic routes) - is ultimately achieved without the need for explicit pharmacophore pattern comparison across the target types to be screened.