7.3.2 Parallel Synthesis of Antiinflammatory Agents from d-Amino Acids
Using a substrate-based approach from glycerophospholipid substrates, we had decided in the 1990s to generate inhibitors of the specific enzyme isoform sPLA2 (Ila) through parallel synthesis methods, starting with simple D-amino acids.29,30 Our preliminary modeling of various putative amino acid derivatives into the reported crystal structure31-33 of sPLA2 (Ila), from the synovial cavity of patients with rheumatoid arthritis, had suggested to us that such an approach might be successful in rapidly generating potent inhibitors. Representative of our attempts are the chiral substrate analogs of the simple D-amino acids (Figure 7.2) and a disclosed set of D-tyrosine derivatives of structure 3 (Table 7.3).
For example, benzyl-protected Boc-D-tyrosine was converted (Scheme 7.3) via the Weinreb amide to an aldehyde before chain extension with methyl/ethyl triphenylphosphoranylidene acetate (S-stereochemistry being confirmed for the amine derivative by Mosher analysis), before sequential deprotection, parallel coupling to phenyl/pyridl alkanoic acid derivatives, hydrogenation over Pd/C in ethyl acetate, and saponification with NaOH to produce inhibitors 3a-3f and, by analogy, 3g.29 Two further steps involving removal of the benzyl group and alylation with alkyl halides in base led to larger analogs 3h-3p. A crystal structure determination29 showed that analog 3b bound in the active site of recombinant human nonpancreatic secretory sPLA2-IIa, the carboxylate and amide carbonyl oxygens chelating as a bidentate ligand to calcium, the amide NH hydrogen bonding to catalytic residue His48, and the phenylhepatanoyl and benzyloxy substituents occupying the large hydrophobic cleft of the enzyme active site. This information was obtained well after the
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