Secretory phospholipase inhibitor

LY311727 is an indole acetic acid based selective inhibitor of human non-pancreatic secretory phospholipase A2 (hnpsPLA2) under development by Lilly as a potential treatment for sepsis. The synthesis of LY311727 involved a Nenitzescu indolization reaction as a key step. The Nenitzescu condensation of quinone 4 with the p-aminoacrylate 39 was carried out in CH3NO2 to provide the desired 5-hydroxylindole 40 in 83% yield. Protection of the 5-hydroxyl moiety in indole 40 was accomplished in H2O under phase transfer conditions in 80% yield. Lithium aluminum hydride mediated reduction of the ester functional group in 41 provided the alcohol 42 in 78% yield. 

RW Schevitz, NJ Bach, DG Carlson, NY Chirgadze, DK Clawson, RD Dillard, SE Draheim, LW Hartley, ND Jones, ED Mihelich, JL Olkowski, DW Snyder, C Sommers, JP Wery. Structure-based design of the first potent and selective inhibitor of human non-pancreatic secretory phospholipase A2. Nat Struct Biol 2 458-465,1995. 

K Kitadokoro, S Hagishita, T Sato, M Ohtani, K Miki. Crystal structure of human secretory phospholipase A2-IIA complex with the potent indolizine inhibitor 120-1032. J Biochem (Tokyo) 123 619-623, 1998. 

XII. Secretory Phospholipase A2 Inhibitors A. (V-Benzyl Tetracyclic-based Medicaments Title sPLA2 Inhibitors... 

The synthesis of the first potent and selective secretory phospholipase Az (S-PLA2) inhibitor, LY311727, was carried out in the laboratory of M.J. Martinelli. The indole core of the target was prepared by the Nenitzescu indole synthesis, which proceeded in high yield. The enamine component was readily prepared from methyl propionylacetate (3-oxo-pentanoic acid methyl ester) and benzylamine in the presence of catalytic amounts of TsOH. A thorough screening of various solvents pinpointed nitromethane as the optimal solvent for the transformation, since the product crystallized from the reaction mixture and was easily removed by filtration. 

Gil, B. Sanz, M. J. Terencio, M. C. Gunasegaran, R. Paya, M. Alcaraz, M. J., Morelloflavone, a novel biflavonoid inhibitor of human secretory phospholipase A2 with anti-inflammatory activity, Biochem. Pharmacol, 1997, 53, 733-740. 

Miheiich, E.D. and Schevitz, R.W. (1999) Structure-based design of a new class of anti-inflammatory drags secretory phospholipase A2 inhibitors, SPI. Biochim. Biophys. Acta 1441 223-228. 

May and colleagues used triphenyl phosphite, which was found to be superior to both trimethyl and triethyl phosphite, to prepare carbazole precursors to the secretory phospholipase A inhibitors LSN433771 and LSN426891 (Scheme 7, equation 1) [68]. Huleatt and Chai and their cowoikers employed the Freeman variation and microwave... 

Dillard RD, Bach NJ, Draheim SE, Berry DR, Carlson DG, Chirgadze NY, et al. Indole inhibitors of human nonpancreatic secretory phospholipase A2. 1. Indole-3-acet-amides./. Med. Chem. 1996 39 5119-5136. 

Hagishita S, Yamada M, Shirahase K, Okada T, Murakami Y, Ito Y, et al. Potent inhibitors of secretory phospholipase A2 Synthesis and inhibitory activities of indolizine and indene derivatives. /. Med. Chem. 1996 39 3636-3658. 

The homology of p36 with lipocortin II and its ability to inhibit pancreatic phospholipase A2 suggests a possible but unproven role as inhibitor of intracellular phospholipase A2 [86]. Phospholipase A2 activity provides one of the many means of arachidonate production which would have important consequences to the activation of secretory response and membrane fusion events. The observation that the 40 kDa protein kinase C substrate, whose phosphorylation state changes dramatically upon platelet activation, may partially cross-react with a polyclonal antibody raised to rat renal lipocortin, is therefore interesting [120]. An alternate sug-... 

Escrig, V., Ubeda, A., Ferrandiz, M.L., Darias, J., Sanchez, J.M., Alcaraz, M.J. and Paya, M. (1997). Vairabilin A dual inhibitor of human secretory and cytosolic phospholipase A2 with anti-inflammatory activity. J. Pharmacol. Exp. Therapeutics 282, 123-131. 

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