title: 1-(5-carboxyindol-1-yl)propan-2-one inhibitors of human cytosolic phospholipase A(2)alpha with reduced lipophilicity: synthesis, biological activity, metabolic stability, solubility, bioavailability, and topical in vivo activity.
abstract: Indole-5-carboxylic acids with 3-aryloxy-2-oxopropyl residues in position 1 were previously reported to be potent inhibitors of human cytosolic phospholipase A(2)alpha (cPLA(2)alpha). In continuation of our attempts to develop clinical active cPLA(2)alpha inhibitors, a series of structurally related indole-5-carboxylic acids with reduced lipophilicity was synthesized and tested for cPLA(2)alpha-inhibitory potency. Furthermore, the thermodynamic solubility of these compounds and their metabolic stability in rat liver microsomes were evaluated. With an IC(50) of 0.012 microM against the isolated enzyme, compound 36 was one of the most potent cPLA(2)alpha inhibitors that emerged during the structure-activity relationship study. Concomitantly, 36 possessed the highest water solubility (212 microg/mL at pH 7.4) of all new target compounds. Despite these favorable properties, peroral application of 36 (100 mg/kg) in mice only led to low concentrations of the substance in blood plasma. A very high plasma clearance was observed after intravenous administration of 36 (10 mg/kg). However, in a topical murine model of contact dermatitis, 36 showed a pronounced anti-inflammatory in vivo activity.
authors.affiliation: Institute of Pharmaceutical and Medicinal Chemistry, University of Munster, Hittorfstrasse 58-62, 48149 Munster, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Drews
authors.forename: Stefanie
authors.initials: S
authors.lastname: Bovens
authors.forename: Kirsten
authors.initials: K
authors.lastname: Roebrock
authors.forename: Cord
authors.initials: C
authors.lastname: Sunderkötter
authors.forename: Dirk
authors.initials: D
authors.lastname: Reinhardt
authors.forename: Michael
authors.initials: M
authors.lastname: Schäfers
authors.forename: Andrea
authors.initials: A
authors.lastname: van der Velde
authors.forename: Alwine
authors.initials: A
authors.lastname: Schulze Elfringhoff
authors.forename: Jörg
authors.initials: J
authors.lastname: Fabian
authors.forename: Matthias
authors.initials: M
authors.lastname: Lehr
mesh_terms: D000287:Administration, Topical; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001646:Bile / Q000378:metabolism; D001682:Biological Availability; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology; D003600:Cytosol / Q000201:enzymology*; D003877:Dermatitis, Contact / Q000188:drug therapy; D004355:Drug Stability; D020719:Glucuronides / Q000378:metabolism; D054513:Group IV Phospholipases A2 / Q000037:antagonists & inhibitors*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000378:metabolism; D010647:Phenyl Ethers / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: C551617:3-isobutanoyl-1-(2-oxo-3-(4-phenoxyphenoxy)propyl)indole-5-carboxylic acid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D020719:Glucuronides; D007211:Indoles; D010647:Phenyl Ethers; D054513:Group IV Phospholipases A2