D‐Tyrosine as a Chiral Precusor to Potent Inhibitors of Human Nonpancreatic Secretory Phospholipase A₂ (IIa) with Antiinflammatory Activity

Abstract

Few reported inhibitors of secretory phospholipase A(2) enzymes truly inhibit the IIa human isoform (hnpsPLA(2)-IIa) noncovalently at submicromolar concentrations. Herein, the simple chiral precursor D-tyrosine was derivatised to give a series of potent new inhibitors of hnpsPLA(2)-IIa. A 2.2-A crystal structure shows an inhibitor bound in the active site of the enzyme, chelated to a Ca(2+) ion through carboxylate and amide oxygen atoms, H-bonded through an amide NH group to His48, with multiple hydrophobic contacts and a T-shaped aromatic-group-His6 interaction. Antiinflammatory activity is also demonstrated for two compounds administered orally to rats.

Antifibrotic Activity of an Inhibitor of Group IIA Secretory Phospholipase A2 in Young Spontaneously Hypertensive Rats

“…The target specificity of any drug in vivo can never be completely certain, but there is considerable evidence that KH064 is a highly target-selective drug. We have reported its crystal structure (pdb code: 1kq) in complex with sPLA 2 -IIA (27), and identified its specific interactions within the unusual active site of that enzyme. In vitro radioligand binding and fluorometric/calorimetric functional assays (D.P.…”

“…This dose was chosen because it was effective in the rat models described above (27)(28)(29). Olive oil-treated SHR and WKY rats served as vehicle controls.…”

“…The present study has investigated whether the sPLA 2 -IIA inhibitor 5-(4-benzyloxyphenyl)-4S-(phenyl-heptanoylamino)-pentanoic acid (designated here as KH064 but referred to as compound "2b" in Ref. 27) prevents cardiovascular remodeling in young male SHR during the development of hypertension. KH064 is an orally active, competitive and reversible inhibitor with high potency (IC 50 29 nM) and selectivity (sPLA 2 -V: IC 50 Ͼ 5 M) for the human sPLA 2 -IIA enzyme (27,28).…”

“…27) prevents cardiovascular remodeling in young male SHR during the development of hypertension. KH064 is an orally active, competitive and reversible inhibitor with high potency (IC 50 29 nM) and selectivity (sPLA 2 -V: IC 50 Ͼ 5 M) for the human sPLA 2 -IIA enzyme (27,28). This inhibitor was effective at 5 mg/kg/day p.o.…”

“…This inhibitor was effective at 5 mg/kg/day p.o. as an anti-inflammatory drug in rat models of adjuvant-induced arthritis (27), intestinal ischemia-reperfusion injury (28), and inflammatory bowel disease (29). KH064 also reduces NOx production from the myocardium, myocardial damage, and cardiomyocyte death during cold ischemia associated with donor heart preservation, and sPLA 2 activation has been implicated in up-regulation of NO synthase-2 during cardiac ischemia (25).…”