A Novel Phospholipid Derivative of Indomethacin, DP-155 [Mixture of 1-Steroyl and 1-Palmitoyl-2-{6-[1-(p-chlorobenzoyl)- 5-methoxy-2-methyl-3-indolyl acetamido]hexanoyl}-sn-glycero- 3-phosophatidyl Choline], Shows Superior Safety and Similar Efficacy in Reducing Brain Amyloid  in an Alzheimer’s Disease Model E. Dvir, J. E. Friedman, J. Y. Lee, J. Y. Koh, F. Younis, S. Raz, I. Shapiro, A. Hoffman, A. Dahan, 1 G. Rosenberg, I. Angel, A. Kozak, and R. Duvdevani D-Pharm Ltd., Rehovot, Israel (E.D., J.E.F., F.Y., S.R., I.S., G.R., I.A., A.K., R.D.); University of Ulsan College of Medicine, Seoul, South Korea (J.Y.L., J.Y.K.); and Department of Pharmaceutics, Hebrew University of Jerusalem, Israel (A.H., A.D.) Received February 20, 2006; accepted June 7, 2006 ABSTRACT Indomethacin has been suggested for the treatment of Alzhei- mer’s disease (AD), but its use is limited by gastrointestinal and renal toxicity. To overcome this limitation, D-Pharm Ltd. (Rehovot, Israel) developed DP-155 (mixture of 1-steroyl and 1-palmitoyl-2- {6-[1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indolyl acetamido] hexanoyl}-sn-glycero-3-phosophatidyl choline), a lecithin deriva- tive of indomethacin. Safety was tested by daily oral administra- tion of DP-155 or indomethacin to rats in a dose range of 0.007 to 0.28 mmol/kg. The prevalence of gastrointestinal ulceration was significantly lower (10-fold) for DP-155 than for indomethacin, and the ulcerations were delayed. Signs of renal toxicity, namely re- duced urine output and increased urine N-acetyl glycosaminidase to creatinine ratio, were 5-fold lower for DP-155. Indomethacin, but not an equimolar dose of DP-155, reduced urine bicyclo- prostaglandin E 2 . An equimolar oral dose of DP-155 or indometh- acin, administered every 4 h for 3 days, was equally efficacious in reducing the levels of A42 in the brains of Tg2576 mice. Indo- methacin was the principal metabolite of DP-155 in the serum. After DP-155 oral administration, indomethacin’s half-life in the serum and the brain was 22 and 93 h, respectively, compared with 10 and 24 h following indomethacin oral administration. The brain to serum ratio was 3.5 times higher for DP-155 than indomethacin. This finding explains the efficacy of DP-155 in reducing A42 brain levels, despite the low systemic blood concentrations of indo- methacin derived from DP-155. In conclusion, compared with indomethacin, DP-155 has significantly lower toxicity in the gut and kidney while maintaining similar efficacy to indomethacin in lowering A42 in the brains of Tg2576 mice. This superior safety profile highlights DP-155’s potential as an improved indometha- cin-based therapy for AD. Indomethacin belongs to the nonsteroidal anti-inflamma- tory drug (NSAID) family. The use of NSAIDs was found to have an inverse correlation with the prevalence and severity of Alzheimer’s disease (AD) in epidemiological and clinical studies (in t’ Veld et al., 2001). Alzheimer’s disease is char- acterized by three pathological hallmarks: extracellular amy- loid  (A) plaques, intracellular neurofibrillary tangles (composed of hyperphosphorylated Tau protein), and neuro- nal and synaptic loss. The pathology development is accom- panied by marked inflammatory processes (microglial and astrocytic reaction) (McGeer and McGeer, 1999). Indometh- acin inhibits A plaque formation via -secretase inhibition, which is a cyclooxygenase (COX)-independent process (Weg- gen et al., 2001). In addition, NSAIDs have COX-dependent anti-inflammatory and neuroprotective effects (Halliday et al., 2000; Weggen et al., 2001). This work was supported by the Israeli Consortium of Pharmalogica and by D-Pharm Ltd. 1 This work is a part of Ph.D. dissertation. Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.106.103184. ABBREVIATIONS: NSAID, nonsteroidal anti-inflammatory drug; AD, Alzheimer’s disease; A, amyloid ; COX, cyclooxygenase; GI, gastrointes- tinal; PGE, prostaglandin E; GFR, glomerular filtration rate; DP-155, mixture of 1-steroyl and 1-palmitoyl-2-{6-[1-(p-chlorobenzoyl)-5-methoxy-2- methyl-3-indolyl acetamido]hexanoyl}-sn-glycero-3-phosophatidyl choline; APP, amyloid precursor protein; NAG, N-acetyl glycosaminidase; ELISA, enzyme-linked immunoassay; ANOVA, analysis of variance; AUC, area under the curve. 0022-3565/06/3183-1248–1256$20.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 318, No. 3 Copyright © 2006 by The American Society for Pharmacology and Experimental Therapeutics 103184/3133586 JPET 318:1248–1256, 2006 Printed in U.S.A. 1248 at ASPET Journals on July 20, 2018 jpet.aspetjournals.org Downloaded from