1,2,4-Oxadiazolidin-3,5-diones and 1,3,5-triazin-2,4,6-triones as cytosolic phospholipase A2α inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 16, Issue 11, 2006, Pages 2978-2981

  Gopalsamy, Ariamala ^a   Yang, Hui ^a   Ellingboe, John W ^a   McKew, John C ^b   Tam, Steve ^b   Joseph McCarthy, Diane ^b   Zhang, Wen ^c   Shen, Marina ^c   Clark, James D ^c  

^a WYETH RESEARCH   (United States)

^b PFIZER INC   (United States)

^c The Inflammation Research Foundation   (United States)

Author keywords

1,2,4 Oxadiazolidin 3,5 dione; 1,3,5 Triazin 2,4,6 trione; Cytosolic phospholipase A2 inhibitors

Indexed keywords

OXADIAZOLE DERIVATIVE; PHOSPHOLIPASE A2 INHIBITOR; PHOSPHOLIPASE A2ALPHA INHIBITOR; TRIAZINE DERIVATIVE; UNCLASSIFIED DRUG;

ARTICLE; CELL ASSAY; CONTROLLED STUDY; DRUG ACTIVITY; DRUG IDENTIFICATION; ENZYME INHIBITION; IC 50; NONHUMAN; RAT; STRUCTURE ACTIVITY RELATION;

ENZYME INHIBITORS; MODELS, MOLECULAR; MOLECULAR STRUCTURE; OXADIAZOLES; PHOSPHOLIPASES A; PROTEIN STRUCTURE, TERTIARY; STRUCTURE-ACTIVITY RELATIONSHIP; SUBSTRATE SPECIFICITY; TRIAZINES;

EID: 33646061599     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2006.02.067     Document Type: Article

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11. Parallel solution-phase synthesis was carried out in 8 mL vials in 0.1 mmol scale using an orbital shaker. Reaction completion was monitored by LC-MS and the solvent was removed in Savant evaporator and compounds were purified by HPLC and the purity was >90%. LC conditions: HP 1100, 23 °C, 10 μL injected; column: YMC-ODS-A 4.6 × 50 mm 5μ; gradient A: 0.05% TFA/water, gradient B: 0.05% TFA/acetonitrile; time: 0 and 1 min: 98% A and 2% B: 7 min: 10% A and 90% B; 8 min: 10% A and 90% B; 8.9 min: 98% A and 2% B; post-time 1 min; flow rate 2.5 mL/min; detection: 215 and 254 nm, DAD. Semi-Prep HPLC: Gilson with Unipoint software; Column: Phenomenex C18 Luna 21.6 mm × 60 mm, 5 μ; solvent A: water (0.02% TFA buffer); solvent B: acetonitrile (0.02% TFA buffer); solvent gradient: time 0: 5% B; 2.5 min: 5% B; 12 min: 95% B; hold 95% B 3 min; flow rate: 22.5 mL/min; detection: 215 and 254 nm.
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18. While Arg 200 is proposed to stabilize the binding of the negatively charged phosphate group of the phospholipid substrate, Ser 228 acts as the nucleophile and attacks the sn-2 ester to form the acyl enzyme intermediate. The oxyanion hole, putatively formed by Gly 197 and Gly 198, polarizes the sn-2 ester and stabilizes the tetrahedral intermediate (see Ref. 10). In the model of 35, the acid group most closely mimics the ester. Models of less potent analogs, with shorter linkers, showed the acid group interacting with Arg 200. However, compounds predicted to bind deeper in the active site cleft showed enhanced affinity.