Organic Health Protocol

Organic Health Protocol

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FIGuRE 7.2 Representative inhibitors of sPLA2 (Ila) derived from amino acids D-tyrosine, D-histidine, D-serine, and D-tryptophan.







CO2Rj sCHEME 7.3 Parallel synthesis of antiinflammatory agents from D-tyrosine. Reagents: (i) BOP, DIPEA, DMF, NHMe(OMe).HCl; (ii) LiAlH4, THF; (iii) Ph3P=CHCO2Me or Ph3P=CHCO2Et, THF; R1 = Me or Et; (iv) Pd/C, H2, EtOAc; (v) (a) TFA, CH2Cl2, (b) BOP, DIPEA, DMF, 7-(3-nitrophenyl)-heptanoic acid, (c) aq. NaOH, THF, MeOH, (d) 1 M HCl; (vi) (a) TFA, CH2Cl2, (b) BOP, DIPEA, DMF, substituted or unsubstituted phenyl- or pyridyl-alkanoic acid, (c) H2, Pd/C, EtOAc, (d) aq. NaOH, THF, MeOH, (e) 1 M HCl, R1 = H; (vii) R1 = Et or Me, (a) H2, Pd/C, THF, HCl, (b) R4-Y (Y = Cl, Br, I), K2CO3, DMF, (c) NaOH, THF, MeOH.

structure-activity relationships had been determined for compounds 3a-3q generated in parallel, but confirmed that the two hydrophobic tails in this series of compounds do fill the hydrophobic cleft of the enzyme.

7.3.3 Enzyme Inhibition and Antiinflammatory Activity

Table 7.3 shows some structure-activity relationships for representative compounds 3a-q as inhibitors of recombinant human nonpancreatic secretory sPLA2-IIa.29 The in vitro colorimetric assay34 utilized a thioester substrate and Ellman's reagent to detect cleavage by enzyme, and the results from this assay have nicely correlated with our in vivo findings of antiinflammatory activity in rats (e.g., against arthritis, ischemia-reperfusion injury, fibrotic disorders, inflammatory bowel diseases, hypertension, uterine contractions, uveitis).2930 Thirteen compounds in Table 7.3 had substantial potency at submicromolar concentrations against the human enzyme, and ten compounds had IC50 values below 250 nM (3b, 3h-3p).

Many compounds covered by our patent30 have been found to be potent and selective inhibitors of sPLA2-IIa over other sPLA2 enzymes. Crystal structures solved for several compounds demonstrated similar binding modes to that for 3b. A key feature was the location of an aromatic ring of the inhibitor within bonding distance of His6,29 which is unique to the human enzyme (not present iv, v


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