Susan Elizabeth Draheim

Indole inhibitors of human nonpancreatic secretory phospholipase A2. 3. Indole-3-glyoxamides.

Phospholipases (PLAs) produce rate-limiting precursors in the biosynthesis of various types of biologically active lipids involved in inflammatory processes. Increased levels of human nonpancreatic secretory phospholipase A2 (hnps-PLA2) have been detected in several pathological conditions. An inhibitor of this enzyme could have therapeutic utility. A broad screening program was carried out to identify chemical structures which could inhibit hnps-PLA2. One of the lead compounds generated by the screening program was 5-methoxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid (13a). We describe the syntheses, structure−activity relationships, and pharmacological activities of a series of indole-3-acetamides and related compounds derived from this lead. This SAR was undertaken with the aid of X-ray crystal structures of complexes between the inhibitors and hnps-PLA2 which were of great value in directing the SAR.

[3.3.0] Pyrazolodinones: An efficient synthesis of a new class of synthetic antibacterial agents.

Abstract A novel synthesis of [3.3.0] fused pyrazolidinones is described. The methodology relies on selective stepwise functionalization of the ring nitrogens of a known pyrazolidinone monocycle. Intramolecular Wadsworth-Horner-Emmons condensation gives rise to the desired bicyclic structure. The compounds prepared from this route have demonstrated potent antibacterial activity in vitro .

Transgenic model for the discovery of novel human secretory non-pancreatic phospholipase A2 inhibitors

Transgenic mice were created which overexpress human secretory non-pancreatic phospholipase A2 (sPLA2) pansomatically as a potential disease and drug-testing model. The mice were produced using a DNA construct in which the inducible mouse metallothionein gene promoter drives expression of a human sPLA2 minigene. High levels of sPLA2 were detected in several tissues by immunofluorescence localization. Expression in the testes caused hypospermia and male infertility. Circulating catalytically active sPLA2 could be induced to levels observed in patients undergoing a systemic inflammatory response but had no detectable effect on the mice. Therefore, these results suggest that sPLA2 hyperphospholipasemia alone may have only limited pathophysiological consequences. We further show that 3-[3-acetamide-1-benzyl-2-ethylindolyl-5-oxy]propane phosphonic acid LY311727), a potent new inhibitor of phospholipase A2 catalysis developed by our group, dramatically suppresses the circulating enzyme activity in these animals whereas 3-[3-acetamide-1-benzyl-2-propylindolyl-5-oxy]propane phosphonic acid (LY314024), a substantially less potent LY311727 analog, is without effect. These later results thus motivate the further development of this compound as a potential new therapeutic agent and valuable research tool.

The chemistry of substituted pyrazolidinones ; applications to the synthesis of bicyclic derivatives

Abstract Methodology for the selective chemical derivatizations of substituted pyrazolidinones is described. The application of these methods to the preparation of [4.3.0] and [3.3.0] bicyclic systems is also discussed. The importance of these latter systems as nuclei of antibacterial agents with potential utility in the treatment of infectious disease provides the motivation for these investigations.

[4.3.0] pyrazolidinones as potential antibacterial agents

Abstract The synthesis of [4.3.0] fused pyrazolidinones is described. The compounds were prepared with substituents identical to those of the known antibacterial agents in the [3.3.0] pyrazolidinone series. Their preparation involved a six-membered ring annulation to a known pyrazolidinone monocycle. Appropriate deblocking and functionalization of the nuclei provided compounds suitable for biological evaluation. In contrast to their lower homologues, the [4.3.0] pyrazolidinones did not exhibit significant antibacterial activity.