Discovery and SAR of PF-4693627, a potent, selective and orally bioavailable mPGES-1 inhibitor for the potential treatment of inflammation

Arhancet, Graciela B.; Walker, Daniel P.; Metz, Sue; Fobian, Yvette M.; Heasley, Steven E.; Carter, Jeffrey S.; Springer, John R.; Jones, Darin E.; Hayes, M.; Shaffer, Alexander F.; Jerome, Gina M.; Baratta, Mike; Zweifel, Ben S.; Moore, William M.; Masferrer, Jaime L.; Vazquez, Michael L.

doi:10.1016/j.bmcl.2012.11.109

Cited by 47 publications

(29 citation statements)

References 13 publications

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“…Again, high lipophilicity and thus tendency for protein binding impaired PGE 2 suppression in human whole blood (IC 50 ≈ 5 µM) [79]. Another HTS hit with a benzoxazole core led to a series of orally active, selective benzoxazole piperidinecarboxamides with IC 50 = 2-3 nM for cell-free mPGES-1 [80].…”

Section: Inhibitors Have Been Reported Yetmentioning

confidence: 98%

“…reduced PGE 2 synthesis in vivo in a guinea pig carrageenan-induced air pouch model without lowering 6-keto-PGF 1α . Since the lead PF-4693627 exhibited most favorable in vitro potency and selectivity (with respect to TxB 2 and PGD 2 ), in vivo efficacy, and a beneficial pharmacokinetic and preclinical safety profile, it was advanced to clinical studies for the treatment of inflammation in osteoarthritis and rheumatoid arthritis [80]. Cmpd.…”

Section: Inhibitors Have Been Reported Yetmentioning

confidence: 99%

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

Koeberle

Werz

2015

Biochemical Pharmacology

112

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Section: Inhibitors Have Been Reported Yetmentioning

confidence: 98%

Section: Inhibitors Have Been Reported Yetmentioning

confidence: 99%

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

Koeberle

Werz

2015

Biochemical Pharmacology

112

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“…The structure–activity optimization of a benzoxazole hit allowed the discovery of PF‐4693627, a benzoxazole piperidinecarboxamide, by Pfizer . PF‐4693627 has exhibited in vitro potency and selectivity against mPGES‐1, along with effectiveness in reducing PGE 2 levels in a carrageenan‐induced air pouch model of inflammation . While PF‐4693627 was still undergoing additional preclinical studies, Pfizer has examined a novel set of substituted benzoxazoles to obtain nonacidic compounds with improved aqueous solubility.…”

Section: Identification Of Novel Targets In the Arachidonic Acid Cascadementioning

confidence: 99%

Nonsteroidal Anti‐Inflammatory Therapy: A Journey Toward Safety

Pereira-Leite

Nunes

Jamal

et al. 2016

Medicinal Research Reviews

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The efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) against inflammation, pain, and fever has been supporting their worldwide use in the treatment of painful conditions and chronic inflammatory diseases until today. However, the long-term therapy with NSAIDs was soon associated with high incidences of adverse events in the gastrointestinal tract. Therefore, the search for novel drugs with improved safety has begun with COX-2 selective inhibitors (coxibs) being straightaway developed and commercialized. Nevertheless, the excitement has fast turned to disappointment when diverse coxibs were withdrawn from the market due to cardiovascular toxicity. Such events have once again triggered the emergence of different strategies to overcome NSAIDs toxicity. Here, an integrative review is provided to address the breakthroughs of two main approaches: (i) the association of NSAIDs with protective mediators and (ii) the design of novel compounds to target downstream and/or multiple enzymes of the arachidonic acid cascade. To date, just one phosphatidylcholine-associated NSAID has already been approved for commercialization. Nevertheless, the preclinical and clinical data obtained so far indicate that both strategies may improve the safety of nonsteroidal anti-inflammatory therapy.

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“…PF-458 [1-(5-chloro-6-(4-chlorophenyl)benzo[d]oxazol-2-yl)-N-((1S,4S)-4-(hydroxymethyl)cyclohexyl)piperidine-4-carboxamide] was prepared from cis-(4-aminocyclohexyl)methanol and the carboxylic acid of methyl 1-[5-chloro-6-(4-chlorophenyl)benzo[d]oxazol-2-yl] piperidine-4-carboxylate (compound 40, Ar ϭ 4-chlorophenyl) as previously described by Arhancet et al (2). Selectivity was examined in experiments performed in accordance with protocols approved by the Ethics Committee of Pfizer.…”

Section: Selectivity Of Pf-458 For Mpges1mentioning

confidence: 99%

Renal effects induced by prolonged mPGES1 inhibition

Salazar

Vazquez

Masferrer

et al. 2014

American Journal of Physiology-Renal Physiology

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The importance of membrane-bound PGE synthase 1 (mPGES1) in the regulation of renal function has been examined in mPGES1-deficient mice or by evaluating changes in its expression. However, it is unknown whether prolonged mPGES1 inhibition induces significant changes of renal function when Na(+) intake is normal or low. This study examined the renal effects elicited by a selective mPGES1 inhibitor (PF-458) during 7 days in conscious chronically instrumented dogs with normal Na(+) intake (NSI) or low Na(+) intake (LSI). Results obtained in both in vitro and in vivo studies have strongly suggested that PF-458 is a selective mPGES1 inhibitor. The administration of 2.4 mg·kg(-1)·day(-1) PF-458 to dogs with LSI did not induce significant changes in renal blood flow (RBF) and glomerular filtration rate (GFR). A larger dose of PF-458 (9.6 mg·kg(-1)·day(-1)) reduced RBF (P < 0.05) but not GFR in dogs with LSI and did not induce changes of renal hemodynamic in dogs with NSI. Both doses of PF-458 elicited a decrease (P < 0.05) in PGE2 and an increase (P < 0.05) in 6-keto-PGF1α. The administration of PF-458 did not induce significant changes in renal excretory function, plasma renin activity, and plasma aldosterone and thromboxane B2 concentrations in dogs with LSI or NSI. The results obtained suggest that mPGES1 is involved in the regulation of RBF when Na(+) intake is low and that the renal effects elicited by mPGES1 inhibition are modulated by a compensatory increment in PGI2. These results may have some therapeutical implications since it has been shown that prolonged mPGES1 inhibition has lower renal effects than those elicited by nonsteroidal anti-inflammatory drugs or selective cyclooxygenase-2 inhibitors.

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Discovery and SAR of PF-4693627, a potent, selective and orally bioavailable mPGES-1 inhibitor for the potential treatment of inflammation

Cited by 47 publications

References 13 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

Nonsteroidal Anti‐Inflammatory Therapy: A Journey Toward Safety

Renal effects induced by prolonged mPGES1 inhibition

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