Milliner KJ

References (4)

Title : The identification of clinical candidate SB-480848: a potent inhibitor of lipoprotein-associated phospholipase A2 - Blackie_2003_Bioorg.Med.Chem.Lett_13_1067
Author(s) : Blackie JA , Bloomer JC , Brown MJ , Cheng HY , Hammond B , Hickey DM , Ife RJ , Leach CA , Lewis VA , Macphee CH , Milliner KJ , Moores KE , Pinto IL , Smith SA , Stansfield IG , Stanway SJ , Taylor MA , Theobald CJ
Ref : Bioorganic & Medicinal Chemistry Lett , 13 :1067 , 2003
Abstract : Modification of the pyrimidone 5-substituent in clinical candidate SB-435495 has given a series of inhibitors of recombinant lipoprotein-associated phospholipase A(2) with sub-nanomolar potency. Cyclopentyl fused derivative 21, SB-480848, showed an enhanced in vitro and in vivo profile versus SB-435495 and has been selected for progression to man.
ESTHER : Blackie_2003_Bioorg.Med.Chem.Lett_13_1067
PubMedSearch : Blackie_2003_Bioorg.Med.Chem.Lett_13_1067
PubMedID: 12643913

Title : The identification of a potent, water soluble inhibitor of lipoprotein-associated phospholipase A2 - Boyd_2001_Bioorg.Med.Chem.Lett_11_701
Author(s) : Boyd HF , Hammond B , Hickey DM , Ife RJ , Leach CA , Lewis VA , Macphee CH , Milliner KJ , Pinto IL , Smith SA , Stansfield IG , Theobald CJ , Whittaker CM
Ref : Bioorganic & Medicinal Chemistry Lett , 11 :701 , 2001
Abstract : Modification of the pyrimidone 5-substituent in a series of 1-((amidolinked)-alkyl)-pyrimidones, lipophilic inhibitors of lipoprotein-associated phospholipase A2, has given inhibitors of nanomolar potency and improved physicochemical properties. Compound 23 was identified as a potent, highly water soluble. CNS penetrant inhibitor suitable for intravenous administration.
ESTHER : Boyd_2001_Bioorg.Med.Chem.Lett_11_701
PubMedSearch : Boyd_2001_Bioorg.Med.Chem.Lett_11_701
PubMedID: 11266173

Title : 2-(Alkylthio)pyrimidin-4-ones as novel, reversible inhibitors of lipoprotein-associated phospholipase A2 - Boyd_2000_Bioorg.Med.Chem.Lett_10_395
Author(s) : Boyd HF , Flynn ST , Hickey DM , Ife RJ , Jones M , Leach CA , Macphee CH , Milliner KJ , Rawlings DA , Slingsby BP , Smith SA , Stansfield IG , Tew DG , Theobald CJ
Ref : Bioorganic & Medicinal Chemistry Lett , 10 :395 , 2000
Abstract : Starting from two weakly active hits from high throughput screening, a novel series of 2-(alkylthio)-pyrimidin-4-ones with high potency and selectivity for lipoprotein-associated phospholipase A2 has been designed. In contrast to previously known inhibitors, these have been shown to act by a non-covalent and substrate competitive mechanism.
ESTHER : Boyd_2000_Bioorg.Med.Chem.Lett_10_395
PubMedSearch : Boyd_2000_Bioorg.Med.Chem.Lett_10_395
PubMedID: 10714508

Title : Lipoprotein-associated phospholipase A2, platelet-activating factor acetylhydrolase, generates two bioactive products during the oxidation of low-density lipoprotein: use of a novel inhibitor - MacPhee_1999_Biochem.J_338 ( Pt 2)_479
Author(s) : Macphee CH , Moores KE , Boyd HF , Dhanak D , Ife RJ , Leach CA , Leake DS , Milliner KJ , Patterson RA , Suckling KE , Tew DG , Hickey DM
Ref : Biochemical Journal , 338 ( Pt 2) :479 , 1999
Abstract : A novel and potent azetidinone inhibitor of the lipoprotein-associated phospholipase A2 (Lp-PLA2), i.e. platelet-activating factor acetylhydrolase, is described for the first time. This inhibitor, SB-222657 (Ki=40+/-3 nM, kobs/[I]=6. 6x10(5) M-1.s-1), is inactive against paraoxonase, is a poor inhibitor of lecithin:cholesterol acyltransferase and has been used to investigate the role of Lp-PLA2 in the oxidative modification of lipoproteins. Although pretreatment with SB-222657 did not affect the kinetics of low-density lipoprotein (LDL) oxidation by Cu2+ or an azo free-radical generator as determined by assay of lipid hydroperoxides (LOOHs), conjugated dienes and thiobarbituric acid-reacting substances, in both cases it inhibited the elevation in lysophosphatidylcholine content. Moreover, the significantly increased monocyte chemoattractant activity found in a non-esterified fatty acid fraction from LDL oxidized by Cu2+ was also prevented by pretreatment with SB-222657, with an IC50 value of 5.0+/-0.4 nM. The less potent diastereoisomer of SB-222657, SB-223777 (Ki=6.3+/-0.5 microM, kobs/[I]=1.6x10(4) M-1.s-1), was found to be significantly less active in both assays. Thus, in addition to generating lysophosphatidylcholine, a known biologically active lipid, these results demonstrate that Lp-PLA2 is capable of generating oxidized non-esterified fatty acid moieties that are also bioactive. These findings are consistent with our proposal that Lp-PLA2 has a predominantly pro-inflammatory role in atherogenesis. Finally, similar studies have demonstrated that a different situation exists during the oxidation of high-density lipoprotein, with enzyme(s) other than Lp-PLA2 apparently being responsible for generating lysophosphatidylcholine.
ESTHER : MacPhee_1999_Biochem.J_338 ( Pt 2)_479
PubMedSearch : MacPhee_1999_Biochem.J_338 ( Pt 2)_479
PubMedID: 10024526