title: BMS-229724 is a tight-binding inhibitor of cytosolic phospholipase A2 that acts at the lipid/water interface and possesses anti-inflammatory activity in skin inflammation models.
abstract: Cytosolic phospholipase A2 (cPLA2) catalyzes the selective release of arachidonic acid from the sn-2 position of phospholipids and is believed to play a key cellular role in the generation of arachidonic acid. BMS-229724 (4-[4-[2-[2-[bis(4-chlorophenyl)methoxy]ethyl-sulfonyl]ethoxy]phenyl]-1,1,1-trifluoro-2-butanone) was found to be a selective inhibitor of cPLA2 (IC50 = 2.8 microM) in that it did not inhibit secreted phospholipase A2 in vitro, nor phospholipase C and phospholipase D in cells. The compound was active in inhibiting arachidonate and eicosanoid production in U937 cells, neutrophils, platelets, monocytes, and mast cells. With a synthetic covesicle substrate system, the dose-dependent inhibition could be defined by kinetic equations describing competitive inhibition at the lipid/water interface. The apparent equilibrium dissociation constant for the inhibitor bound to the enzyme at the interface (K(I)*(app)) was determined to be 1. 10(-5) mol% versus an apparent dissociation constant for the arachidonate-containing phospholipid of 0.35 mol%. The unit of concentration in the interface is mole fraction (or mol%), which is related to the surface concentration of substrate, rather than bulk concentration that has units of molarity. Thus, BMS-229724 represents a novel inhibitor of cPLA2, which partitions into the phospholipid bilayer and competes with phospholipid substrate for the active site. This potent inhibition of the enzyme translated into anti-inflammatory activity when applied topically (5%, w/v) to a phorbol ester-induced chronic inflammation model in mouse ears, inhibiting edema and neutrophil infiltration, as well as prostaglandin and leukotriene levels in the skin. In hairless guinea pigs, BMS-229724 was active orally (10 mg/kg) in a UVB-induced skin erythema model in hairless guinea pigs.
authors.affiliation: Dermatology Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543, USA. james.burke@bms.com
authors.forename: J R
authors.initials: JR
authors.lastname: Burke
authors.forename: L B
authors.initials: LB
authors.lastname: Davern
authors.forename: P L
authors.initials: PL
authors.lastname: Stanley
authors.forename: K R
authors.initials: KR
authors.lastname: Gregor
authors.forename: J
authors.initials: J
authors.lastname: Banville
authors.forename: R
authors.initials: R
authors.lastname: Remillard
authors.forename: J W
authors.initials: JW
authors.lastname: Russell
authors.forename: P J
authors.initials: PJ
authors.lastname: Brassil
authors.forename: M R
authors.initials: MR
authors.lastname: Witmer
authors.forename: G
authors.initials: G
authors.lastname: Johnson
authors.forename: J A
authors.initials: JA
authors.lastname: Tredup
authors.forename: K M
authors.initials: KM
authors.lastname: Tramposch
mesh_terms: D000284:Administration, Oral; D000287:Administration, Topical; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002273:Carcinogens; D002722:Chlorobenzenes / Q000494:pharmacology / Q000627:therapeutic use; D015232:Dinoprostone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004890:Erythema / Q000188:drug therapy / Q000378:metabolism; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D051379:Mice; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D010703:Phorbol Esters; D010741:Phospholipases A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054467:Phospholipases A2; D010743:Phospholipids / Q000378:metabolism*; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012867:Skin; D013450:Sulfones / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000893:Anti-Inflammatory Agents; C430920:BMS 229724; D002273:Carcinogens; D002722:Chlorobenzenes; D010703:Phorbol Esters; D010743:Phospholipids; D010972:Platelet Activating Factor; D013450:Sulfones; D007975:Leukotriene B4; D010741:Phospholipases A; D054467:Phospholipases A2; D015232:Dinoprostone