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Halopemide, a phospholipase D2 inhibitor identified by high-throughput screening. In January 2007 Monovich and co-workers at Novartis identified halopemide, via a highthroughput screen, as an inhibitor of phospholipase D2 (PLD2) [1]. This was a major feat, as the PLD field suffered from a lack of ligands to probe its biological function; indeed, the gold standard PLD inhibitor is n-butanol. Phospholipase D (PLD) is present in mammalian cells in two distinct isoforms, PLD1 and PLD2 [2,3]. Both PLD isoforms catalyze the hydrolysis of the phosphodiester bond of phosphatidylcholine, thereby forming free choline and phosphatidic acid [2-4]. PLD has been shown to be involved in regulating the actin cytoskeleton, vesicle trafficking, and receptor signaling [3]. PLD itself has been shown to be regulated by phosphatidylinositol-4,5-bisphosphate, protein kinase C, ADP Ribosylation Factor, and the Rho family GTPases [3]. Several disease processes are thought be linked to PLD activity, including cancer and inflammation [5]. A sizeable body of evidence exists that shows elevated PLD expression is often correlated with oncogenesis and metastasis [5]. While a firm mechanistic understanding of PLD’s role in cancer has not yet been elucidated PLD is thought to contribute to Raf recruitment, cell cycle checkpoint override, the suppression of apoptosis, and protease secretion and increased cell motility [5]. In some cases the activity of only one PLD isoform is relevant. For example, only PLD2 activity has been shown to be elevated in renal cell carcinoma [2,6]. Due to the burgeoning body of evidence implicating PLD in cancer and inflammatory diseases, and the frequent observance of elevated PLD expression and activity in various tumors PLD ought to be a favorable molecular target for therapeutic intervention [1,5].

Halopemide was originally reported by Janssen in the 1970's as a potential therapy for autism or other neurological conditions [1, 7]. Recently, Monovich and co-workers from Novartis reported parallel synthesis and relatively modest optimization of halopemide analogs for PLD2 inhibition. Thirteen compounds are disclosed, all of which are actually analogs of deschloro-halopemide. Deschloro-halopemide showed PLD2 potency comparable to halopemide (1.4 μM versus 1.500 μM, respectively) [1]. Monovich and coworkers synthesized 13 analogs in which the amide portion of the molecule was varied [1]. By replacing the pfluorophenyl moiety with a 2-indolyl moiety potency was improved from 1.4 μM to 20.0 nM [1]. The 5-fluoro-2- indolyl compound showed moderate oral bioavailability (18.5%) in rats, and while the compound had a high clearance of 2.18 Lh-1kg-1 it also had a half-life of 5.57 h [1]. Also, a Cmax more than 10 times the IC50 was obtained when the 5-fluoro-2-indolyl compound was dosed at 5 mg/kg p.o. or 1 mg/kg iv [1]. The results from this initial optimization project are encouraging, but a better understanding of the pharmacology of these compounds, and other analogs, would provide more progress toward developing these molecules into a pre-clinical candidate for indications such as cancer and inflammation. Specifically, data on potency in various cell types expressing PLD1 and/or PLD2, cell invasion assay data, and in vivo pharmacology data from animal disease models would be very informative. The work of Monovich and co-workers may lead to progress in understanding the pharmacology of a relatively new molecular target, PLD, in diseases such as cancer and inflammation and represents a significant advance in the PLD field.


[1] Monovich, L.; Mugrage, B.; Quadros, E.; Toscano, K.; Tommasi, R.; LaVoie, S.; Liu, E.; Du, Z.; LaSala, D.; Boyar, W.; Steed, P. ‘Optimization of Halopemide for Phospholipase D2 inhibition’ Bioorg. Med. Chem. Lett. 2007, 17(8), 2310-2311.

[2] McDermott, M.; Wakelam, M.; Morris, A. ‘Phospholipase D’ Biochem. Cell Biol. 2004, 82, 225-253.

[3] Jenkins, G.M.; Frohman, M.A.; ‘Phospholipase D: a lipid centric review’ Cell. Mol. Life Sci. 2005, 62, 2305-2316.

[4] Saito M. and Kanfer J. ‘Phosphatidohydrolase activity in a solubilized preparation from rat brain particulate fraction’ Arch. Biochem. Biophys. 1975, 169, 318-323.

[5] Foster, D.A.; Xu, L. ‘Phospholipase D in Cell Proliferation and Cancer’ Molecular Cancer Research 2003, 1, 789-800.

[6] Zhao, Y., Ehara, H., Akao, Y., Shamoto, M., Nakagawa, Y., Banno, Y., Deguchi, T., Ohishi, N., Yagi, K., and Nozawa, Y. ‘Increased activity and intranuclear expression of phospholipase D2 in renal cancer’ Biochem. Biophys. Res. Commun. 2000, 278, 140-143.

[7] Loonen, A.J.M.; Wijngaarden, I.V.; Janssen, P.A.J.; Soundijn, W. ‘Regional localization of halopemide, a new psychotropic agent, in the rat brain’ European Journal of Pharmacology 1978, 50, 403- 408.
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Document Type: Research Article

Affiliations: Vanderbilt University,Vanderbilt University Medical Center Departments of Pharmacology and Chemistry Robinson Research Buliding 804 Nashville, TN 37232-6600,USA.

Publication date: March 1, 2008

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