Identification of 2-oxo-N-(phenylmethyl)-4-imidazolidinecarboxamide antagonists of the P2X7 receptor

Abberley, Lee; Bebius, Aude; Beswick, Paul J.; Billinton, Andy; Collis, Katharine L.; Dean, David K.; Fonfría, Elena; Gleave, Robert J.; Medhurst, Stephen J.; Michel, Anton D.; Moses, Andrew P.; Patel, Sadhana; Roman, Shilina; Scoccitti, Tiziana; Smith, Beverley; Steadman, Jon G.A.; Walter, Daryl S.

doi:10.1016/j.bmcl.2010.09.101

Cited by 28 publications

(34 citation statements)

References 27 publications

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“…Collectively, these studies support the potential use of dogs in future studies of P2X7. In this regard, laboratories of GlaxoSmithKline (GSK) and Pfizer have already used dogs to assess the pharmacokinetics and bioavailability of P2X7 antagonists, including 2-oxo-N-(phenylmethyl)-4-imidazolidinecarboxamide analogs (Abberley et al, 2010) and 2-(4-chloro-3-[3-(1-hydroxycycloheptyl)propanoyl] phenyl)-4-[(2R)-2-hydroxy-3-methoxy-propyl]-1,2,4-triazine-3,5-dione (CE-224,535) (Duplantier et al, 2011), respectively. The pharmacokinetics and bioavailability of these compounds in dogs were similar to that observed for monkeys (Abberley et al, 2010;Duplantier et al, 2011) and thus potentially similar to that of humans.…”

Section: B the Canine P2x7 Receptormentioning

confidence: 99%

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The P2X7 Receptor Channel: Recent Developments and the Use of P2X7 Antagonists in Models of Disease

2014

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Section: B the Canine P2x7 Receptormentioning

confidence: 99%

“…Thus, it may be of value to explore if the therapeutic benefit of P2X7 blockade is influenced by methotrexate or sulfasalazine resistance. In the meantime, the trial of AZD9056 or CE-224,535 in other human disorders and the trial of other compounds, such as those from GSK (Abberley et al, 2010) and Johnson & Johnson (Bhattacharya et al, 2013), await.…”

mentioning

confidence: 99%

The P2X7 Receptor Channel: Recent Developments and the Use of P2X7 Antagonists in Models of Disease

2014

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“…Selectivity and in vitro activity at heterologously expressed human (and partly rat) P2X7 receptors has been shown for A-804598 and further compounds from Abbott [150–152], AZ11645373 [153]; several compounds from GlaxoSmithKline [154–156]; and compounds from Pfizer [157]. The newly developed nanomolar potent P2X7 receptor-selective antagonists GSK314181A (and further GSK compounds), A-740003, A-438079, and A-839977 have in addition been shown to have in vivo analgesic effects in rodent models of inflammatory pain [158–164].…”

Section: Pharmacological Characteristics Of P2x Receptorsmentioning

confidence: 99%

Molecular and functional properties of P2X receptors—recent progress and persisting challenges

Kaczmarek-Hájek

Lörinczi

Hausmann

et al. 2012

Purinergic Signalling

197

202

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ATP-gated P2X receptors are trimeric ion channels that assemble as homo- or heteromers from seven cloned subunits. Transcripts and/or proteins of P2X subunits have been found in most, if not all, mammalian tissues and are being discovered in an increasing number of non-vertebrates. Both the first crystal structure of a P2X receptor and the generation of knockout (KO) mice for five of the seven cloned subtypes greatly advanced our understanding of their molecular and physiological function and their validation as drug targets. This review summarizes the current understanding of the structure and function of P2X receptors and gives an update on recent developments in the search for P2X subtype-selective ligands. It also provides an overview about the current knowledge of the regulation and modulation of P2X receptors on the cellular level and finally on their physiological roles as inferred from studies on KO mice.

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“…Originally developed by GlaxoSmithKline, GSK1482160 is a potent P2X 7 antagonist with excellent biological activity {PIC 50 8.5 (IC 50 3 nM) for human P2X 7 , and PIC 50 6.6 for rat P2X 7 }. [18][19][20] This compound readily crosses the bloodbrain barrier (BBB), and has been evaluated as a therapeutic agent in a Phase 1 human study, [18][19][20] making it an attractive candidate for possible translation to a PET diagnostic agent.…”

mentioning

confidence: 99%

Synthesis of [11C]GSK1482160 as a new PET agent for targeting P2X7 receptor

Gao

Wang

Green

et al. 2015

Bioorganic & Medicinal Chemistry Letters

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Abstract-The authentic standards GSK1482160 and its isomer, as well as the radiolabeling precursors desmethyl-GSK1482160 and Boc-protected desmethyl-GSK1482160 were synthesized from L-pyroglutamic acid, methyl L-pyroglutamate and 2-chloro-3-(trifluoromethyl)benzylamine with overall chemical yield 27-28% in 3 steps, 58% in 4 steps, 76% in 1 step and 33% in 2 steps, respectively. [11 C]GSK1482160 was prepared from either desmethyl-GSK1482160 or Boc-protected desmethyl-GSK1482160 with [11 C]CH 3 OTf through N-[ 11 C]methylation and isolated by HPLC combined with SPE in 40-50% and 30-40% radiochemical yield, respectively, based on [ 11 C]CO 2 and decay corrected to end of bombardment (EOB). The radiochemical purity was >99%, and the specific activity at EOB was 370-1110 GBq/mol with a total synthesis time of ~40-minutes from EOB.

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Identification of 2-oxo-N-(phenylmethyl)-4-imidazolidinecarboxamide antagonists of the P2X7 receptor

Cited by 28 publications

References 27 publications

The P2X7 Receptor Channel: Recent Developments and the Use of P2X7 Antagonists in Models of Disease

The P2X7 Receptor Channel: Recent Developments and the Use of P2X7 Antagonists in Models of Disease

Molecular and functional properties of P2X receptors—recent progress and persisting challenges

Synthesis of [11C]GSK1482160 as a new PET agent for targeting P2X7 receptor

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