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 β in an Alzheimer's Disease Model

Abstract

Indomethacin has been suggested for the treatment of Alzheimer'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 derivative of indomethacin. Safety was tested by daily oral administration 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 reduced 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 bicycloprostaglandin E 2 . An equimolar oral dose of DP-155 or indomethacin, administered every 4 h for 3 days, was equally efficacious in reducing the levels of A␤42 in the brains of Tg2576 mice. Indomethacin 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 indomethacin 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 indomethacin-based therapy for AD.Indomethacin belongs to the nonsteroidal anti-inflammatory 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 characterized by three pathological hallmarks: extracellular amyloid ␤ (A␤) plaques, intracellular neurofibrillary tangles (composed of hyperphosphorylated Tau protein), and neuronal and synaptic loss. The pathology development is accompanied by marked inflammatory processes (microglial and astrocytic reaction) (McGeer and McGeer, 1999). Indomethacin inhibits A␤ plaque formation via ␥-secretase inhibition, which is a cyclooxygenase (COX)-independent process (Weggen et al., 2001). In addition, NSAIDs have COX-dependent anti-inflammatory and neuroprotective effects (Halliday et al., 2000;Weggen et al., 2001 ABBREVIATIONS: NSAID, nonsteroidal anti-inflammatory drug; AD, Alzheimer's disease; A␤, amyloid ␤; COX, cyclooxygenase; GI, gastrointestinal; PGE, prostaglandin E; GFR, glomerular filtration rate; DP-155, mixture of 1-steroyl and 1-palmitoyl-2-{6-[1-(p-chlorobenzoyl...

1-(3′,4′-Dichloro-2-fluoro[1,1′-biphenyl]-4-yl)-cyclopropanecarboxylic Acid (CHF5074), a Novel γ-Secretase Modulator, Reduces Brain β-Amyloid Pathology in a Transgenic Mouse Model of Alzheimer's Disease without Causing Peripheral Toxicity

“…At 15 months of age, the SDS-extractable A␤ represents approximately 10% of the A␤ pool extracted by FA (Kawarabayashi et al, 2001). Because ␥-secretase modulators are thought to mainly affect SDS-extractable A␤ pools, i.e., the newly formed A␤ (Yan et al, 2003;Dvir et al, 2006), a double SDS extraction was performed in an attempt to maximize this A␤ fraction. Indeed, the double SDS-extracted A␤ in our study represented 46 to 47% of the total extracted A␤.…”

“…A␤40 and A␤42 were extracted from brain by using both the SDS and formic acid (FA) methods. Because ␥-secretase modulators are thought to affect mainly SDS-extractable A␤ pools, i.e., the newly formed A␤ (Yan et al, 2003;Dvir et al, 2006), a double SDS extraction was performed in an attempt to maximize SDS-extractable A␤. One hemisphere was first homogenated in 2% SDS in water [100 mg/ml (wet w/v)] containing protease inhibitors (Complete Protease Inhibitor Cocktail; Roche Diagnostics, Basel, Switzerland) and an aliquot of 500 l was centrifuged at 16,000g for 10 min.…”

31P Magnetic Resonance Spectroscopy of Endothelial Cells Grown in Three-Dimensional Matrigel Constructs as an Enabling Platform Technology: II. The Effect of Anti-Inflammatory Drugs on Phosphometabolite Levels

“…The ability of indomethacin to block COX activity, which may help to mitigate endothelial injury in response to hypoxia (Gloria et al 2006), may provide an additional reason for its inclusion in the construct. Furthermore, it has been shown that DP-155 selectively inhibits the inducible COX-2 but not the constitutively active COX-1 (Dvir et al 2006), a property that may further contribute to the selective anti-inflammatory effects of the drug.…”

“…One approach to reduce the adverse effects of NSAIDs is the use of a prodrug strategy (Rodriguez-Tellez et al 2001). We took advantage of a newly developed indomethacin prodrug (DP-155; Dvir et al 2006) to study its effects on the 31 P MRS phospholipid profile of ECs grown in 3D Matrigel threads. DP-155 ( Figure 3A) consists of the parental drug indomethacin ( Figure 3B) coupled through a lipidic linker (DP-499; Figure 3C) to phosphatidylcholine (PtdC; Figure 3D).…”

“…Lipidic prodrugs are molecules composed of the drug, which is covalently bound to a lipid moiety. The lipid prodrug approach has been employed with few NSAIDs, including aspirin (Kumar and Billimoria 1978), indomethacin (Dvir et al 2006), and naproxen (Sugihara et al 1988), to improve penetration through biological barriers and to reduce toxicity (Lambert 2000). This approach has not yet been investigated with vascularized tissue-engineered constructs.…”