Secretory phospholipase

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. 

Synaptic stimulation, ischemia or seizure activates phospholipase A2 and releases arachidonic and docosahexaenoic acids 578 Secretory phospholipases A2 are of relatively low molecular weight and have a high number of disulfide bridges, making them relatively more resistant to denaturation 579 There are high-affinity receptors that bind secretory phospholipase A2 579... 

Lambeau, G., Ancian, P., Barhanin, J. and Lazdunski, M. Cloning and expression of a membrane receptor for secretory phospholipases A2. / Biol. Chem. 269 1575-1578,1994. 

Kolko, M., DeCoster, M. A., Rodriguez de Turco, E. B. and Bazan, N. G. Synergy by secretory phospholipase A2 and glutamate on inducing cell death and sustained arachidonic acid metabolic changes in primary cortical neuronal cultures./. Biol. Chem. 271 32722-32728,1996. 

Anthonsen, M.W., Stengel, D., Hourton, D., Ninio, E., Johansen, B., 2000, Mildly oxidized LDL induces expression of group 11a secretory phospholipase A(2) in human monocyte-derived macrophages, Arterioscler Thromb Vase Biol, 20 1276-1282. 

Jensen SS, Andresen TL, Davidsen J, et al. Secretory phospholipase A2 as a tumor-specific trigger for targeted delivery of a novel class of liposomal prodrug anticancer ether lipids. Mol Cancer Ther 2004 3 1451-1458. 

Bridonneau, P., Chang, Y.F., O Connell, D., Gill, S, C., Snyder, D.W., Johnson, L., Goodson, T. Jr., Herron, D.K. and Parma, D.H. (1998) High-affinity aptamers selectively inhibit human nonpancreatic secretory phospholipase A2 (hnps-PLA2), 3. Med. Chem. 41,118-786. 

Thwin M. M., Ong W. Y., Fong C. W., Sato K., Kodama K., Farooqui A. A., and Gopalakrishnakone P. (2003). Secretory phospholipase A2 activity in the normal and kainate injected rat brain, and inhibition by a peptide derived from python serum. Exp. Brain Res. 150 427-433. 

Yegin A., Akbas S. H., Ozben T., and Korgun D. K. (2002). Secretory phospholipase A2 and phospholipids in neural membranes in an experimental epilepsy model. Acta Neurol. Scand. 106 258-262. 

SPLA2, secretory phospholipase A2 COX-2, inducible nitric oxide synthase iNOS, inducible nitric oxide synthase SOD, superoxide dismutase ICAM-1, intracellular adhesion molecule-1 VCAM-1, vascular adhesion molecule-1 TNF-a, tumor necrosis factor-a IL, interleukin and MMP, matrix metalloproteinases. 

Fig. 8.1 A schematic diagram illustrating the involvement of NF-k I in gpl20, ROS, NO, PG, IL-1/3 and TNF-a-mediated neurotoxicity. NMDA-R, N-Methyl-D-aspartate receptor, cPLA2, cytosolic phospholipase A2 lyso-PtdCho, lysophosphatidylcholine AA, arachidonic acid cAMP, cyclic adenosine monophosphate PKA, protein kinase A TNF-a, tumor necrosis factor-a TNF-a-R, TNF-a-receptor IL-1/8, interleukin-1 /3 IL-l/i-R, IL-1/8-receptor, IL-6, interleukin-6 MARK, mitogen-activated protein kinase NO, nitric oxide PG, prostaglandins EP-R, prostaglandin receptors NF-kB, nuclear factor-icB NF-kB-RE, nuclear factor-/cB-response element I/cB, inhibitory subunit of NF-icB HIV-1, human immunodeficiency virus type 1 gpl20, HIV-1 coat glycoprotein COX-2, cyclooxygenase-2 iNOS, inducible nitric oxide synthase SPLA2, secretory phospholipase A2 SOD, superoxide dismutase MMP, matrix metalloproteinase and VCAM-1, vascular adhesion molecule-1...

Andresen TL, Jensen SS, Kaasgaard T, Jorgensen K. Triggered activation and release of liposomal prodmgs and drugs in cancer tissue by secretory phospholipase A2. Curr Drug Deliv. 2005 2 353-362. 

DL Scott, SP White, JL Browning, JJ Rosa, MH Gelb, PB Sigler. Structures of free and inhibited human secretory phospholipase A2 from inflammatory exudate. Science 254 1007-1010, 1991. 

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. 

M Murakami, S Shimbara, T Kambe, H Kuwata, MV Winstead, JA Tischfield, I Kudo. The functions of five distinct mammalian phospholipase A2s in regulating arachidonic acid release. Type IIA and type V secretory phospholipase A2s are functionally redundant and act in concert with cytosolic phospholipase A2. J Biol Chem 273 14411-14423, 1998. 

Pruzanski, W., Urowitz, M. B., Grouix, B., and Vadas, P. (1995). Induction of TNF-alpha and proinflammatory secretory phospholipase A2 by intravenous administration of CAMPATH-1H in patients with rheumatoid arthritis. /. Rheumatol. 22, 1816-1819. 

Fluhr, J.W. et al., Stratum corneum acidification in neonatal skin secretory phospholipase A2 and the sodium/hydrogen antiporter-1 acidify neonatal rat stratum corneum, J. Invest. Dermatol., 122, 320, 2004. 

Murakami, M., Kambe, T., Shimbara, S., Higashino, K., Hanasaki, K., Arita, H., Horiguchi, M., Arita, M., Arai, H., Inoue, K. and Kudo, I., 1999, Different functional aspects ofthe group II subfamily (Types IIA and V) and type X secretory phospholipase A(2)s in regulating arachidonic add release and prostaglandin generation. Implications of cyclooxygenase-2 induction and phospholipid scramblase-mediated cellular membrane perturbation../. Biol. Chem., 274 31435-31444. 

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

Invention Significance Human nonpancreatic secretory phospholipase-A2... 

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