Pharmacological Characterization of SC-57461A (3-[Methyl[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoic Acid HCl), a Potent and Selective Inhibitor of Leukotriene A4Hydrolase I: In Vitro Studies
- Leslie J. Askonas,
- James F. Kachur,
- Doreen Villani-Price,
- Chi-Dean D. Liang,
- Mark A. Russell and
- Walter G. Smith
- Leslie J. Askonas, Pharmacia Research and Development, 4901 Searle Parkway, Skokie, IL 60077. E-mail: leslie.j.askonas{at}pharmacia.com
Abstract
Leukotriene (LT) B4 is an inflammatory mediator that has been implicated in the pathogenesis of various diseases, including inflammatory bowel disease and psoriasis. As the rate-limiting step for LTB4 production, LTA4 hydrolase represents an attractive target for therapeutic agents that interfere with LTB4 production. In the present study we evaluated a chemically novel compound designated SC-57461A (3-[methyl[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoic acid HCl) as an inhibitor of LTA4 hydrolase. Pharmacological comparisons are made to its free acid SC-57461. SC-57461A is a potent competitive inhibitor of recombinant human LTA4 hydrolase when either LTA4(IC50 = 2.5 nM, Ki = 23 nM) or peptide substrates (IC50 = 27 nM) are used. In human whole blood, the IC50 for calcium ionophore-induced LTB4 production was 49 nM, indicative of good cell penetration. Whole blood production of the cyclooxygenase metabolite thromboxane B2 was not affected. SC-57461A was also active in several other species, including mouse, rat, dog, and rhesus monkey. The data indicate that SC-57461A is a potent and selective inhibitor of LTA4 hydrolase.
Footnotes
- Abbreviations:
- LT
- leukotriene
- SC-57461A
- 3-[methyl[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoic acid HCl
- LTA4
- 5(S)-trans-5,6-oxido-7,9-trans-11,14-cis-eicosatetraenoic acid
- LTB4
- 5(S),12(R)-dihydroxy-6,14-cis-8,10-trans-eicosatetraenoic acid
- 5-LO
- 5-lipoxygenase
- rhLTA4
- recombinant human leukotriene A4 hydrolase
- ELISA
- enzyme-linked immunosorbent assay
- BSA
- bovine serum albumin
- DMSO
- dimethyl sulfoxide
- RP-HPLC
- reversed phase-high-performance liquid chromatography
- pNA
- p-nitroanilide
- TxB2
- thromboxane B2
- A23187
- calcium ionophore A23187(Calcimycin)
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- Received July 17, 2001.
- Accepted November 2, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
