William A. Metz

Design of Potent IGF1‐R Inhibitors Related to Bis‐azaindoles

From an azaindole lead, identified in high throughput screen, a series of potent bis‐azaindole inhibitors of IGF1‐R have been synthesized using rational drug design and SAR based on a in silico binding mode hypothesis. Although the resulting compounds produced the expected improved potency, the model was not validated by the co‐crystallization experiments with IGF1‐R.

A convenient synthesis of peptidyl perfluoroalkyl ketones

Abstract A convenient method is described for the preparation of α-amino perfluoroalkyl ketones via direct nucleophilic perfluoroalkylation of the corresponding peptide ester. This method was used to prepare dehydrovaline pentafluoroethyl ketone 2 from the corresponding N -Boc-protected dehydrovaline methyl ester 3 . Similar α-amino esters, N -Boc-valine methyl ester 4 , Boc-Valyl-prolyl-dehydrovaline methyl ester 8a and Boc-valyl-prolyl-valine methyl ester 8b were also converted directly to the corresponding pentafluoroethyl ketones 6 , 9a and 9b . The method was also applied to the synthesis of heptafluoropropyl- and nonafluorobutyl peptidyl ketones 11a and 11b from their corresponding esters, albeit in lower yield. These amino ketones are useful as intermediates in the preparation of peptidyl perfluoroalkyl ketones which have been shown to be potent inhibitors of human neutrophil elastase.

Synthesis of (E)-3-(2-carboxy-2-pyridyl-vinyl)-4,6-dichloro-1H-indole-2-carboxylic acids, glycine-site NMDA receptor antagonists, utilizing the Knoevenagel condensation reaction

Abstract The Knoevenagel condensation of arylacetonitriles with ethyl 4,6-dichloro-3-formyl-1 H -indole-2-carboxylate ( 2 ), followed by hydrolysis, provides a convenient entry into a series of analogs of MDL 105,519, 1 , a selective glycine site N -methyl- d -aspartate (NMDA) receptor antagonist. Surprisingly, the hydrolysis of the indole arylpropenenitriles terminates at the formation of the corresponding carboxamide and does not proceed further to the desired dicarboxylic acid. However, when the aryl substituent is pyridine, hydrolysis proceeds via an azepinoindole unique to this series, which upon further hydrolysis converts smoothly to the desired dicarboxylic acid analog.