N-(Carboxymethyl)-N-[3,5-bis(decyloxy)phenyl]glycine (Ro 23-9358): a potent inhibitor of secretory phospholipases A2 with antiinflammatory activity

LeMahieu, Ronald A.; Carson, M.; Han, Ru-Jen; Madison, Vincent; Hope, William C.; Chen, Ting; Morgan, Douglas W.; Hendrickson, H. Stewart

doi:10.1021/jm00072a025

Cited by 28 publications

(19 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In recent assays, mainly human recombinant enzymes hve been used, as mentioned in respective passages below. The sequences and structures, characteristics, activation, regulation, and sources of these various enzymes have been reviewed and outlined extensively [6][7][8][9][17][18][19][20][21][22][23][24][25][26][27][30][31][32][33][34][35][36][38][39][40][41][42][43]53,[91][92][93][94][95][96]. …”

Section: Enzyme Assaysmentioning

confidence: 99%

“…Rat adjuvant arthritis has been used as a model to study the effects of PLA2 inhibitors on T-cell mediated immunologic processes [28,29,91]. Models of reperfusion injury or disturbed myocardial perfusion for testing inhibitors of myocardial plasmalogen specific iPLA2 have been reported [31,32].…”

Section: In Vivo Modelsmentioning

confidence: 99%

“…Ro-23-9358 (N-(carboxymethyl)-N-(3,5-bis (decyloxy)phenyl)glycine; Roche) is a particularly active member of a series of inhibitors designed by means of the uncomplexed crystallographic structure of bovine pancreatic PLA 2 and an interactive molecular graphics programme [91]. Ro-23-9358 was described as a reversible active site-directed inhibitor of h-sPLA2 [91].…”

Section: Ro-23-9358mentioning

confidence: 99%

“…Ro-23-9358 was described as a reversible active site-directed inhibitor of h-sPLA2 [91]. Because it is a dicarboxylic acid like BMS-181162 it may bind to the Ca 2+ atom in the active site of the enzyme.…”

Section: Ro-23-9358mentioning

confidence: 99%

“…Because it is a dicarboxylic acid like BMS-181162 it may bind to the Ca 2+ atom in the active site of the enzyme. Ro-23-9358 was shown to be an inhibitor of a crude human synovial PLA2 preparation with an IC50 of 230 nM (scooting mode assay) [91]. Its IC50 against recombinant human placental PLA2 is 87 nM [91].…”

Section: Ro-23-9358mentioning

confidence: 99%

See 4 more Smart Citations

Phospholipase A2 inhibitors in development

Tibes

1997

Expert Opinion on Investigational Drugs

View full text Add to dashboard Cite

To date, three isoforms of phospholipase A2 (PLA2) have been identified. Of these, the two Ca2+-dependent isoforms, secretory (sPLA2) and cytosolic phospholipase A2 (cPLA2), are targets for new anti-inflammatory drugs. The catalytic mechanisms and functions of the third isoform, Ca2+-independent cytosolic phospholipase A2 (iPLA2), are unknown at present. sPLA2 and cPLA2 are both implicated in the release of arachidonic acid and prophlogistic lipid mediators. However, recent findings provide evidence that cPLA2 is the dominant isoform in various kinds of inflammation, such as T-cell-mediated experimental arthritis. A triple function of PLA2-derived lipid mediators has been suggested: causing immediate inflammatory signs, involvement in secondary processes, e.g., superoxide free radical (O2) generation, apoptosis, or tumour necrosis factor-alpha (TNF-alpha)-cytotoxicity, and controlling the expression and activation of pivotal proteins implicated in inflammation and cell development, e.g., cytokines, adhesion proteins, proteinases, NF-kappaB, fos/jun/AP-1, c-Myc, or p21ras. In the past, research predominantly focused on the development of sPLA2 inhibitors; however, present techniques enable discrimination of cPLA2, sPLA2, and iPLA2, and specific inhibitors of each of the three isoforms are likely to appear soon. Over the last decade, between 40 and 50 sPLA2 inhibitors have been described; and the list is growing. However, of these, few have the potential for clinical success, and those that do are predominantly active site-directed inhibitors, e.g., BMS-181162, LY311727, ARL-67974, FPL67047, SB-203347, Ro-23-9358, YM-26734, and IS-741. At present, there are no likely clinical candidates emerging from the ranks of cPLA2 and iPLA2 inhibitors in development. Indications for which PLA2 inhibitors are being pursued include, sepsis, acute pancreatitis, inflammatory skin and bowel diseases, asthma, and rheumatoid arthritis. The three main obstacles to the successful development of PLA2 inhibitors include, insufficient oral bioavailability, low affinity for the enzyme corresponding to low in vivo efficacy and insufficient selectivity.

show abstract

Section: Enzyme Assaysmentioning

confidence: 99%

Section: In Vivo Modelsmentioning

confidence: 99%

Section: Ro-23-9358mentioning

confidence: 99%

Section: Ro-23-9358mentioning

confidence: 99%

Section: Ro-23-9358mentioning

confidence: 99%

See 3 more Smart Citations

Phospholipase A2 inhibitors in development

Tibes

1997

Expert Opinion on Investigational Drugs

View full text Add to dashboard Cite

show abstract

A molecular dynamics study of the three‐dimensional model of human synovial fluid phospholipase A ₂ —transition state mimic complexes

Hariprasad

Kulkarni

1996

J. Mol. Recognit.

View full text Add to dashboard Cite

Different modes of binding of transition state mimics: amide, phosphonate and difluoro ketone, to human synovial fluid phospholipase A2 (HSF PLA2) are studies by molecular dynamics simulations computed in solvent. The results are analysed in the light of primary binding sites. Hydrogen bonding interaction plays an important role for amino acids such as Gly32, Val30, and Glu55, apart from the well known active site residues viz Asp48, Gly25, Gly29, Gly31, His27, His47, Lys62, Phe23, Asn114 and Tyr112. In addition, the hydrogen bonding interaction between Sn-1 tetrahedral phosphonate group of amide and difluoro ketone inhibitors and crystallographic water molecules (H2O 523, H2O 524 and H2O 401) seems to have a significant role. Many of the active site charged residues display considerable movement upon ligand binding. The structural effects of ligand binding were analyzed from RMS deviations of C alpha in the resulting energy-minimized average structures of the receptor-ligand complexes. The values of the RMS deviations differ among the HSF PLA2s, in a pattern that is not the same for the three complexes. This suggests that ligands with different pharmacological efficacies induce different types of conformational changes of the receptor. Our active-orientation model is, at least qualitatively, consistent with experimental data and should be useful for the rational design of more potent inhibitors.

show abstract

Crystal structures of the complexes of a group IIA phospholipase A₂ with two natural anti‐inflammatory agents, anisic acid, and atropine reveal a similar mode of binding

et al. 2006

View full text Add to dashboard Cite

Secretory low molecular weight phospholipase A(2)s (PLA(2)s) are believed to be involved in the release of arachidonic acid, a precursor for the biosynthesis of pro-inflammatory eicosanoids. Therefore, the specific inhibitors of these enzymes may act as potent anti-inflammatory agents. Similarly, the compounds with known anti-inflammatory properties should act as specific inhibitors. Two plant compounds, (a) anisic acid (4-methoxy benzoic acid) and (b) atropine (8-methyl-8-azabicyclo oct-3-hydroxy-2-phenylpropanoate), have been used in various inflammatory disorders. Both compounds (a) and (b) have been found to inhibit PLA(2) activity having binding constants of 4.5 x 10(-5) M and 2.1 x 10(-8) M, respectively. A group IIA PLA(2) was isolated and purified from the venom of Daboia russelli pulchella (DRP) and its complexes were made with anisic acid and atropine. The crystal structures of the two complexes (i) and (ii) of PLA(2) with compounds (a) and (b) have been determined at 1.3 and 1.2 A resolutions, respectively. The high-quality observed electron densities for the two compounds allowed the accurate determinations of their atomic positions. The structures revealed that these compounds bound to the enzyme at the substrate - binding cleft and their positions were stabilized by networks of hydrogen bonds and hydrophobic interactions. The most characteristic interactions involving Asp 49 and His 48 were clearly observed in both complexes, although the residues that formed hydrophobic interactions with these compounds were not identical because their positions did not exactly superimpose in the large substrate-binding hydrophobic channel. Owing to a relatively small size, the structure of anisic acid did not alter upon binding to PLA(2), while that of atropine changed significantly when compared with its native crystal structure. The conformation of the protein also did not show notable changes upon the bindings of these ligands. The mode of binding of anisic acid to the present group II PLA(2) is almost identical to its binding with bovine pancreatic PLA(2) of group I. On the other hand, the binding of atropine to PLA(2) is similar to that of another plant alkaloid aristolochic acid.

show abstract

N-(Carboxymethyl)-N-[3,5-bis(decyloxy)phenyl]glycine (Ro 23-9358): a potent inhibitor of secretory phospholipases A2 with antiinflammatory activity

Cited by 28 publications

References 7 publications

Phospholipase A2 inhibitors in development

Phospholipase A2 inhibitors in development

A molecular dynamics study of the three‐dimensional model of human synovial fluid phospholipase A ₂ —transition state mimic complexes

Crystal structures of the complexes of a group IIA phospholipase A₂ with two natural anti‐inflammatory agents, anisic acid, and atropine reveal a similar mode of binding

Contact Info

Product

Resources

About

N-(Carboxymethyl)-N-[3,5-bis(decyloxy)phenyl]glycine (Ro 23-9358): a potent inhibitor of secretory phospholipases A2 with antiinflammatory activity

Cited by 28 publications

References 7 publications

Phospholipase A2 inhibitors in development

Phospholipase A2 inhibitors in development

A molecular dynamics study of the three‐dimensional model of human synovial fluid phospholipase A 2 —transition state mimic complexes

Crystal structures of the complexes of a group IIA phospholipase A2 with two natural anti‐inflammatory agents, anisic acid, and atropine reveal a similar mode of binding

Contact Info

Product

Resources

About

A molecular dynamics study of the three‐dimensional model of human synovial fluid phospholipase A ₂ —transition state mimic complexes

Crystal structures of the complexes of a group IIA phospholipase A₂ with two natural anti‐inflammatory agents, anisic acid, and atropine reveal a similar mode of binding