title: Convergent and enantioselective syntheses of cytosolic phospholipase A(2)α inhibiting N-(1-indazol-1-ylpropan-2-yl)carbamates.
abstract: Cytosolic phospholipase A2α (cPLA2α) is an important enzyme of the inflammation cascade. Therefore, inhibitors of cPLA2α are assumed to be promising drug candidates for the treatment of inflammatory disorders. Recently we have found that indole-5-carboxylic acid with a 3-(4-octylphenoxy)-2-(phenoxycarbonylamino)propyl substituent in position 1 is an inhibitor of cPLA2α. We have now synthesized a corresponding derivative with the indole heterocycle replaced by an indazole (4) employing an analogous reaction sequence as for the synthesis of the indole derivative. Besides, a more convergent synthesis for 4 was established using an aziridine as central intermediate. Furthermore, a chiral-pool based enantioselective synthesis was developed for the synthesis of (R)- and (S)-4. Starting compound for both enantiomers was the (R)-serine derived oxazolidine (R)-25. Compound 4 proved to be a moderate inhibitor of cPLA2α, with the S-enantiomer being twice as active as the R-enantiomer. The racemate 4 and the enantiomers (R)- and (S)-4 showed a high in vitro metabolic stability in rat liver S9 fractions.
authors.affiliation: Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Corrensstrasse 48, D-48149 Münster, Germany. lehrm@uni-muenster.de.
authors.forename: Tom
authors.initials: T
authors.lastname: Sundermann
authors.forename: Martina
authors.initials: M
authors.lastname: Arnsmann
authors.forename: Julian
authors.initials: J
authors.lastname: Schwarzkopf
authors.forename: Walburga
authors.initials: W
authors.lastname: Hanekamp
authors.forename: Matthias
authors.initials: M
authors.lastname: Lehr
mesh_terms: D000818:Animals; D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004795:Enzyme Stability / Q000187:drug effects; D054513:Group IV Phospholipases A2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D013237:Stereoisomerism; D034421:Sus scrofa
chemical_list: D002219:Carbamates; D054513:Group IV Phospholipases A2