Discovery of disubstituted phenanthrene imidazoles as potent, selective and orally active mPGES-1 inhibitors

Giroux, André; Boulet, Louise; Brideau, Christine; Chau, Anh; Claveau, David; Côté, Bernard; Ethier, Diane; Frenette, Richard; Gagnon, Marc; Guay, Jocelyne; Guiral, Sébastien; Mancini, Joseph A.; Martins, Evelyn; Massé, Frédéric; Méthot, Nathalie; Riendeau, Denis; Rubin, Joel; Xu, Daigen; Yu, Hongping; Ducharme, Yves; Friesen, Richard W.

doi:10.1016/j.bmcl.2009.08.085

Cited by 60 publications

(37 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Subsequent MF-63 derivatives possessed up to 10-fold higher efficiency in human whole blood (IC 50 = 0.14 µM) and exhibited higher efficacy in a guinea pig hyperalgesia model at 14 mg/kg, p.o. [76]. Nevertheless, to our knowledge, further reports about MF-63 or related phenanthrene derivatives have not been published since 2009, and the current development status of these promising inhibitors is unknown.…”

Section: Page 23 Of 59mentioning

confidence: 87%

Perspective of microsomal prostaglandin E2 synthase-1 as drug target in inflammation-related disorders

Koeberle

Werz

2015

Biochemical Pharmacology

111

View full text Add to dashboard Cite

Section: Page 23 Of 59mentioning

confidence: 87%

Perspective of microsomal prostaglandin E2 synthase-1 as drug target in inflammation-related disorders

Koeberle

Werz

2015

Biochemical Pharmacology

111

View full text Add to dashboard Cite

“…MF63 typifies a rapidly expanding line of compounds [7,14,17,18] that, by interfering selectively with the main PGE synthase, hold great promise as a research tool and mechanism-based therapeutic agent. Significantly, our result was obtained in an animal model bearing human mPGES1, hence overcoming any difficulty due to particular, structure-linked differences among species in Contractile responses to ( a ) MF63 ؒ HCl, 10 M , in the control animal and ( b ) L -NAME, 100 M , before and after chronic pretreatment with MF63 (10 mg kg -1 twice daily for 3 days).…”

Section: Discussionmentioning

confidence: 99%

“…However, contrary to expectations, a dilator effect not involving NO followed chronic treatment. Hence, the nature of this vasodilatory component needs to be defined before considering this or allied compounds [14] for treatment of infants with PDA.…”

mentioning

confidence: 99%

Dual, Constrictor-to-Dilator, Response of the Mouse Ductus Arteriosus to the Microsomal Prostaglandin E Synthase-1 Inhibitor, 2-(6-Chloro-1H-phenanthro[9,10<i>d</i>]imidazole- 2-yl)isophthalonitrile

et al. 2011

Self Cite

View full text Add to dashboard Cite

Background: Microsomal prostaglandin E synthase-1 (mPGES1) is critical for prostaglandin E₂ formation in ductus arteriosus (DA) and, accordingly, in its patency. We previously reported that mPGES1 deletion, unlike cyclo-oxygenase (COX) suppression, is not followed by upregulation of relaxant nitric oxide (NO). Consequently, we proposed that a mPGES1 inhibitor may be better than currently used COX inhibitors in managing premature infants with persistent DA (PDA). Objective: To assess the effect of the mPGES1 inhibitor, 2-(6-chloro-1H-phenanthro[9,10d]imidazole-2-yl)isophthalonitrile (MF63) on DA ex vivo and in vivo (p.o. to the mother). Methods: Experiments were carried out with mice bearing human mPGES1. We utilized isolated, wire-mounted DA for isometric recording and a whole-body freezing technique to assess the DA caliber as it occurs in vivo. Results: MF63 (10 µM) contracted the isolated DA. DA constriction was also seen in vivo after a single 10-mg kg^–1 dose. Conversely, a 30-mg kg^–1 dose gave inconsistent results, combining constriction with no effect. DA dilatation followed instead a repeated lower dose (twice daily for 3 days), and postnatal closure of the vessel was also delayed. Chronic pretreatment had no effect on endothelial NO synthase mRNA expression in fetal DA, nor did it modify the contraction to NO synthase inhibitor N^G-nitro-L-arginine methyl ester (100 µM). Conclusions: MF63 has a dual action on DA, the constriction being associated with accessory dilatation. The latter effect should be explained before considering further a mPGES1 inhibitor for management of PDA.

show abstract

“…Merck Frosst reported the development of a number of novel ring templates as potent and selective mPGES-1 inhibitors [80,81,82]. An indole based agent ( 28 , Figure 7), possessing a COOH group exhibited potent mPGES-1 inhibition (mPGES-1 IC 50 = 0.007 µM) and effective PGE 2 inhibition (IC 50 = 8.0 µM) in cell based assays [80].…”

Section: Mpges-1 Inhibitorsmentioning

confidence: 99%

“…In an extension of this work, a disubstituted phenanthrene imidazole ( 30 , Figure 7) containing a propargylic tertiary alcohol moiety was developed that exhibited potent and selective mPGES-1 inhibition (mPGES-1 IC 50 = 0.001 µM; mPGES-2 IC 50 > 30 µM) and oral activity in lipopolysaccharide (LPS)-induced hyperalgesia guinea pig model (ED 50 = 30 mg/kg). Interestingly, 30 exhibited a long in vivo pharmacokinetic properties in a rat model (t 1/2 = 20 h) relative to 29 [82]. …”

Section: Mpges-1 Inhibitorsmentioning

confidence: 99%

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Progress in Small Molecule Drug Development

2010

View full text Add to dashboard Cite

Ever since the discovery of aspirin, small molecule therapeutics have been widely prescribed to treat inflammation and pain. Aspirin and several small molecule NSAIDs are known to inhibit the enzymes cyclooxygenase-1 (COX-1) and -2 (COX-2). Despite the success of NSAIDs to treat inflammatory disorders, the development of a clinically useful small molecule NSAIDs with decreased side effect profiles is an ongoing effort. The recent discovery and development of selective COX-2 inhibitors was a step toward this direction. Emerging trends are represented by the progress in the development of hybrid agents such as nitric oxide donor-NSAIDs (NO-NSAIDs) and dual COX/lipoxygenase (LOX) inhibitors. This review focuses on the recent advances in the rational design of small molecule NSAIDs in therapy.

show abstract

Discovery of disubstituted phenanthrene imidazoles as potent, selective and orally active mPGES-1 inhibitors

Cited by 60 publications

References 20 publications

Perspective of microsomal prostaglandin E2 synthase-1 as drug target in inflammation-related disorders

Perspective of microsomal prostaglandin E2 synthase-1 as drug target in inflammation-related disorders

Dual, Constrictor-to-Dilator, Response of the Mouse Ductus Arteriosus to the Microsomal Prostaglandin E Synthase-1 Inhibitor, 2-(6-Chloro-1H-phenanthro[9,10<i>d</i>]imidazole- 2-yl)isophthalonitrile

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Progress in Small Molecule Drug Development

Contact Info

Product

Resources

About