Biochemical, Functional, and Pharmacological Characterization of AT-56, an Orally Active and Selective Inhibitor of Lipocalin-type Prostaglandin D Synthase

Pivotal Role of Reactive Oxygen Species in Differential Regulation of Lipopolysaccharide-Induced Prostaglandins Production in Macrophages

“…PGD synthases have been reported, namely H-PGDS and L-PGDS (Matsushita et al, 1998a,b;Irikura et al, 2009). Our data showed that pretreatment of BMDM with MnTMPyP (50 mM; Fig.…”

“…HQL-79 and AT-56 are reported isoformselective PGDS inhibitors interdicting H-PGDS-and L-PGDS-mediated PGD 2 production both in vivo and in vitro, respectively (Matsushita et al, 1998a,b;Irikura et al, 2009). ROS are chemical reactive molecules containing oxygen generated during normal and disease-related metabolic processes (Xiao et al, 2002;Bedard and Krause, 2007), including three major species superoxide (O 2…”

Activation of adipogenesis by lipocalin-type prostaglandin D synthase-generated Δ12-PGJ2 acting through PPARγ-dependent and independent pathways

“…In summary, Δ 12 -PGJ 2 was found to be the major metabolite of PGD 2 in differentiated adipocytes, and L-PGDS-generated Δ 12 -PGJ 2 activated (Irikura et al, 2009) the progression of adipogenesis through both PPARγ-dependent and -independent mechanisms in 3T3-L1 cells. Elevation of adiponectin and leptin production by Δ 12 -PGJ 2 .…”

“…PGD 2 -overproducing mice become obese when on a high-fat diet (Fujitani et al, 2010), indicating that an L-PGDS inhibitor might have potential as an inhibitor of adipogenesis. Recently, 4-dibenzo[a,d]cyclohepten-5-ylidene-1-[4-(2H-tetrazol-5-yl)-butyl]-piperidine (AT-56) was shown to be an L-PGDS inhibitor (Irikura et al, 2009). PGD 2 is known to undergo spontaneous dehydration to PGs of Jseries such as PGJ 2 , Δ 12 -PGJ 2 and 15-deoxy Δ 12,14 -PGJ 2 (15d-PGJ 2 ).…”

Competitive Enzymatic Interactions Determine the Relative Amounts of Prostaglandins E2 and D2

“…PGD synthase activity is also comprised of two isozymes, H-PGDS and L-PGDS. propyl-piperidine; C 22 H 27 N 5 O] is a selective H-PGDS inhibitor (Matsushita et al, 1998a,b), and d]cyclohepten-5-ylidene)-1- [4-(2H-tetrazol-5-yl) butyl]-piperidine; C 25 H 27 N 5 ] is reported to be a selective L-PGDS inhibitor (Irikura et al, 2009).…”