Mark P. Healy

Remarkable anion effects uncovered in the development of a Au(III)-catalyzed tandem nucleophilic substitution–1,5-enyne cycloisomerization process

(I(t)Pe)AuBr(2)(N-imidate) complexes, prepared in high yield by oxidative bromination, are active catalysts for 1,5-enyne cycloisomerization. An efficient tandem nucleophilic substitution-1,5-enyne cycloisomerization is promoted by these novel Au(III) precatalysts. Catalyst efficacy is affected by the imidate ligand and the silver salt used (e.g. Ag[Al(OC(CF(3))(3))(4)]).

Pyrazolopyridazine alpha-2-delta-1 ligands for the treatment of neuropathic pain

Optimization of the novel alpha-2-delta-1 ligand 4 provided compounds 37 and 38 which have improved DMPK profiles, good in vivo analgesic activity and in vitro selectivity over alpha-2-delta-2. An in-house P-gp prediction programme and the MetaSite software package were used to help solve the specific problems of high P-gp efflux and high in vivo clearance.

Discovery of GSK1997132B a novel centrally penetrant benzimidazole PPARγ partial agonist

The peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated nuclear receptor, thought to play a role in energy metabolism, glucose homeostasis and microglia-mediated neuroinflammation. A novel benzimidazole series of centrally penetrant PPARγ partial agonists has been identified. The optimization of PPARγ activity and in vivo pharmacokinetics leading to the identification of GSK1997132B a potent, metabolically stable and centrally penetrant PPARγ partial agonist, is described.

Mechanistic examination of AuIII-mediated 1,5-enyne cycloisomerization by AuBr2(N-imidate)(NHC)/AgX precatalysts – is the active catalyst AuIII or AuI?

Gold(III) catalysts mediate 1,5-enyne cycloisomerization or tandem nucleophilic substitution-1,5-enyne cycloisomerization processes in an efficient manner. This study examines the reaction kinetics of 1,5-enyne cycloisomerization, mediated by AuBr2(N-imidate)(NHC) catalysts {where N-imidate = N-tetrafluorosuccinimide (N-TFS) or N-phthalimide (N-phthal) and NHC = N,N′-di-tert-pentylimidazol-2-ylidene (ItPe)}, in the presence of AgOTf, in comparison with AuIIIBr3(NHC) and AuIBr(NHC). The nature of N-imidate anion influences catalyst efficacy. NMR spectroscopic investigations have allowed the ease of reduction of AuBr2(N-TFS)(NHC) to AuIX(NHC) (where X = N-TFS or Br) to be examined. Br2 is liberated from AuIII, which has been trapped by a sacrificial alkene. Under working catalyst conditions cationic AuIII is reduced to AuI.

Discovery of {4-[4,9-bis(ethyloxy)-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl]-2-fluorophenyl}acetic acid (GSK726701A), a novel EP 4 receptor partial agonist for the treatment of pain

A novel series of EP4 agonists and antagonists have been identified, and then used to validate their potential in the treatment of inflammatory pain. This paper describes these novel ligands and their activity within a number of pre-clinical models of pain, ultimately leading to the identification of the EP4 partial agonist GSK726701A.

P2-329: Lowering of brain and plasma Abeta42 in rats using gamma-secretase modulators

have focused on the use of neuroprotective agents, which can decrease A levels, several of which have also been found to regulate synaptic activity. Colivelin is a novel synthetic hybrid peptide that has been shown to have neuroprotective effects against familial AD (FAD) genes and A peptides in vitro, ameliorating functional memory impairment of mice induced soluble toxic amyloidin vivo. Methods: Field excitatory postsynaptic potentials in the CA1 region of acute mouse hippocampal slices were recorded to monitor the potential role of colivelin on synaptic plasticity. Results: We found that the application of colivelin caused a significant enhancement (p 0.05) of basal synaptic transmission at concentrations as low as 10 pM. Conclusions: Our results indicate that colivelin may play a role in basal synaptic transmission at the Schaffer collateral-CA1 synapse through a presynaptic mechanism. Our study also suggests that colivelin may ameliorate cognitive dysfunction prior to the onset of AD pathology.