|
Inhibitory activity against Lp-PLA2 in whole human plasma
|
None
|
5.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The identification of clinical candidate SB-480848: a potent inhibitor of lipoprotein-associated phospholipase A2.
Year : 2003
Volume : 13
Issue : 6
First Page : 1067
Last Page : 1070
Authors : 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.
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.
|
Inhibitory activity against recombinant human Lp-PLA2
|
None
|
0.25
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The identification of clinical candidate SB-480848: a potent inhibitor of lipoprotein-associated phospholipase A2.
Year : 2003
Volume : 13
Issue : 6
First Page : 1067
Last Page : 1070
Authors : 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.
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.
|
Non specific binding effect against Lp-PLA2 was determined in human plasma at 10 nM
|
None
|
60.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The identification of clinical candidate SB-480848: a potent inhibitor of lipoprotein-associated phospholipase A2.
Year : 2003
Volume : 13
Issue : 6
First Page : 1067
Last Page : 1070
Authors : 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.
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.
|
Inhibitory activity against recombinant human Lp-PLA2 by mechanistic studies
|
None
|
0.11
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The identification of clinical candidate SB-480848: a potent inhibitor of lipoprotein-associated phospholipase A2.
Year : 2003
Volume : 13
Issue : 6
First Page : 1067
Last Page : 1070
Authors : 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.
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.
|
Inhibition of Lp-PLA2 within the atherosclerotic plaque 2 hr after an oral dose of 30 mg/kg to the WHHL rabbit
|
Oryctolagus cuniculus
|
95.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The identification of clinical candidate SB-480848: a potent inhibitor of lipoprotein-associated phospholipase A2.
Year : 2003
Volume : 13
Issue : 6
First Page : 1067
Last Page : 1070
Authors : 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.
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.
|
Non specific binding effect against Lp-PLA2 was determined in rabbit plasma at 100 nM
|
Oryctolagus cuniculus
|
79.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The identification of clinical candidate SB-480848: a potent inhibitor of lipoprotein-associated phospholipase A2.
Year : 2003
Volume : 13
Issue : 6
First Page : 1067
Last Page : 1070
Authors : 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.
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.
|
Inhibition of human plasma Lp-PLA2 at 1 nM by liquid scintillation counting
|
Homo sapiens
|
80.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of imidazole and triazole derivatives as Lp-PLA₂ inhibitors and the unexpected discovery of highly potent quaternary ammonium salts.
Year : 2013
Volume : 23
Issue : 5
First Page : 1187
Last Page : 1192
Authors : Wang K, Xu W, Liu Y, Zhang W, Wang W, Shen J, Wang Y.
Abstract : New Lp-PLA(2) inhibitors were synthesized by the bioisosteric replacement of the amide group of Darapladib with an imidazole or a triazole. Unfortunately, the inhibitory activities of these derivatives were lower than that of Darapladib. But interestingly, a series of quaternary ammonium salts that were isolated as by-products during this synthetic work were found with high potency. Of these by-products, compound 22c showed a similar profile to Darapladib both in vitro and in vivo.
|
Inhibition of human plasma Lp-PLA2 at 10 nM by liquid scintillation counting
|
Homo sapiens
|
95.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of imidazole and triazole derivatives as Lp-PLA₂ inhibitors and the unexpected discovery of highly potent quaternary ammonium salts.
Year : 2013
Volume : 23
Issue : 5
First Page : 1187
Last Page : 1192
Authors : Wang K, Xu W, Liu Y, Zhang W, Wang W, Shen J, Wang Y.
Abstract : New Lp-PLA(2) inhibitors were synthesized by the bioisosteric replacement of the amide group of Darapladib with an imidazole or a triazole. Unfortunately, the inhibitory activities of these derivatives were lower than that of Darapladib. But interestingly, a series of quaternary ammonium salts that were isolated as by-products during this synthetic work were found with high potency. Of these by-products, compound 22c showed a similar profile to Darapladib both in vitro and in vivo.
|
Inhibition of rabbit plasma Lp-PLA2 at 10 nM by liquid scintillation counting
|
Oryctolagus cuniculus
|
82.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of imidazole and triazole derivatives as Lp-PLA₂ inhibitors and the unexpected discovery of highly potent quaternary ammonium salts.
Year : 2013
Volume : 23
Issue : 5
First Page : 1187
Last Page : 1192
Authors : Wang K, Xu W, Liu Y, Zhang W, Wang W, Shen J, Wang Y.
Abstract : New Lp-PLA(2) inhibitors were synthesized by the bioisosteric replacement of the amide group of Darapladib with an imidazole or a triazole. Unfortunately, the inhibitory activities of these derivatives were lower than that of Darapladib. But interestingly, a series of quaternary ammonium salts that were isolated as by-products during this synthetic work were found with high potency. Of these by-products, compound 22c showed a similar profile to Darapladib both in vitro and in vivo.
|
Inhibition of rabbit plasma Lp-PLA2 at 100 nM by liquid scintillation counting
|
Oryctolagus cuniculus
|
99.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of imidazole and triazole derivatives as Lp-PLA₂ inhibitors and the unexpected discovery of highly potent quaternary ammonium salts.
Year : 2013
Volume : 23
Issue : 5
First Page : 1187
Last Page : 1192
Authors : Wang K, Xu W, Liu Y, Zhang W, Wang W, Shen J, Wang Y.
Abstract : New Lp-PLA(2) inhibitors were synthesized by the bioisosteric replacement of the amide group of Darapladib with an imidazole or a triazole. Unfortunately, the inhibitory activities of these derivatives were lower than that of Darapladib. But interestingly, a series of quaternary ammonium salts that were isolated as by-products during this synthetic work were found with high potency. Of these by-products, compound 22c showed a similar profile to Darapladib both in vitro and in vivo.
|
Inhibition of recombinant human Lp-PLA2 using [3H]PAF as substrate at 10 nM incubated for 5 mins prior to substrate addition measured after 10 mins by liquid scintillation counting analysis
|
Homo sapiens
|
0.1
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Triazole derivatives: a series of Darapladib analogues as orally active Lp-PLA2 inhibitors.
Year : 2013
Volume : 23
Issue : 10
First Page : 2897
Last Page : 2901
Authors : Wang K, Xu W, Zhang W, Mo M, Wang Y, Shen J.
Abstract : This Letter reports our efforts towards the optimization of our previously identified series of imidazole and triazole derivatives that lead to the discovery of a series of orally active Lp-PLA2 inhibitors in C57 mice. These inhibitors are characterized by the presence of a diamine side chain in the molecules, such as 2c, 2f, and 4a. The introduction of the terminal-end amine succeeded in maintaining the in vitro activities at sub-nanomolar levels. The vivo activities could be greatly affected by variations in the two amines via modulating the metabolic stability and lipophilicity of the compounds.
|
Inhibition of Lp-PLA2 in human plasma using [3H]PAF as substrate at 10 nM incubated for 5 mins prior to substrate addition measured after 10 mins by liquid scintillation counting analysis relative to control
|
Homo sapiens
|
95.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Triazole derivatives: a series of Darapladib analogues as orally active Lp-PLA2 inhibitors.
Year : 2013
Volume : 23
Issue : 10
First Page : 2897
Last Page : 2901
Authors : Wang K, Xu W, Zhang W, Mo M, Wang Y, Shen J.
Abstract : This Letter reports our efforts towards the optimization of our previously identified series of imidazole and triazole derivatives that lead to the discovery of a series of orally active Lp-PLA2 inhibitors in C57 mice. These inhibitors are characterized by the presence of a diamine side chain in the molecules, such as 2c, 2f, and 4a. The introduction of the terminal-end amine succeeded in maintaining the in vitro activities at sub-nanomolar levels. The vivo activities could be greatly affected by variations in the two amines via modulating the metabolic stability and lipophilicity of the compounds.
|
Inhibition of Lp-PLA2 in rabbit plasma using [3H]PAF as substrate at 10 nM incubated for 5 mins prior to substrate addition measured after 10 mins by liquid scintillation counting analysis relative to control
|
Oryctolagus cuniculus
|
82.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Triazole derivatives: a series of Darapladib analogues as orally active Lp-PLA2 inhibitors.
Year : 2013
Volume : 23
Issue : 10
First Page : 2897
Last Page : 2901
Authors : Wang K, Xu W, Zhang W, Mo M, Wang Y, Shen J.
Abstract : This Letter reports our efforts towards the optimization of our previously identified series of imidazole and triazole derivatives that lead to the discovery of a series of orally active Lp-PLA2 inhibitors in C57 mice. These inhibitors are characterized by the presence of a diamine side chain in the molecules, such as 2c, 2f, and 4a. The introduction of the terminal-end amine succeeded in maintaining the in vitro activities at sub-nanomolar levels. The vivo activities could be greatly affected by variations in the two amines via modulating the metabolic stability and lipophilicity of the compounds.
|
Inhibition of Lp-PLA2 in rabbit plasma using [3H]PAF as substrate at 100 nM incubated for 5 mins prior to substrate addition measured after 10 mins by liquid scintillation counting analysis relative to control
|
Oryctolagus cuniculus
|
99.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Triazole derivatives: a series of Darapladib analogues as orally active Lp-PLA2 inhibitors.
Year : 2013
Volume : 23
Issue : 10
First Page : 2897
Last Page : 2901
Authors : Wang K, Xu W, Zhang W, Mo M, Wang Y, Shen J.
Abstract : This Letter reports our efforts towards the optimization of our previously identified series of imidazole and triazole derivatives that lead to the discovery of a series of orally active Lp-PLA2 inhibitors in C57 mice. These inhibitors are characterized by the presence of a diamine side chain in the molecules, such as 2c, 2f, and 4a. The introduction of the terminal-end amine succeeded in maintaining the in vitro activities at sub-nanomolar levels. The vivo activities could be greatly affected by variations in the two amines via modulating the metabolic stability and lipophilicity of the compounds.
|
Inhibition of Lp-PLA2 (unknown origin)
|
Homo sapiens
|
0.25
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of a Novel Series of Imidazo[1,2-a]pyrimidine Derivatives as Potent and Orally Bioavailable Lipoprotein-Associated Phospholipase A2 Inhibitors.
Year : 2015
Volume : 58
Issue : 21
First Page : 8529
Last Page : 8541
Authors : Chen X, Xu W, Wang K, Mo M, Zhang W, Du L, Yuan X, Xu Y, Wang Y, Shen J.
Abstract : Inhibition of lipoprotein-associated phospholipase A2 (Lp-PLA2) has been suggested to be a promising therapeutic strategy for several inflammation-associated diseases, including atherosclerosis, Alzheimer's disease, and diabetic macular edema. Herein, we report the discovery of a novel series of Lp-PLA2 inhibitors constructed on an imidazo[1,2-a]pyrimidine scaffold through a conformational restriction strategy. Structure-activity relationship (SAR) analysis resulted in the identification of several compounds with high potency in vitro and good metabolic stability in liver S9 fractions. Compounds 7c and 14b selected for further exploration in vivo demonstrated excellent pharmacokinetic profiles and exhibited significant inhibitory efficacy in SD rats upon oral dosing.
|
Invivo inhibition of Lp-PLA2 in mouse plasma at 100 nM after 24 hrs
|
Mus musculus
|
96.0
%
|
|
Journal : J. Med. Chem.
Title : Discovery of a Novel Series of Imidazo[1,2-a]pyrimidine Derivatives as Potent and Orally Bioavailable Lipoprotein-Associated Phospholipase A2 Inhibitors.
Year : 2015
Volume : 58
Issue : 21
First Page : 8529
Last Page : 8541
Authors : Chen X, Xu W, Wang K, Mo M, Zhang W, Du L, Yuan X, Xu Y, Wang Y, Shen J.
Abstract : Inhibition of lipoprotein-associated phospholipase A2 (Lp-PLA2) has been suggested to be a promising therapeutic strategy for several inflammation-associated diseases, including atherosclerosis, Alzheimer's disease, and diabetic macular edema. Herein, we report the discovery of a novel series of Lp-PLA2 inhibitors constructed on an imidazo[1,2-a]pyrimidine scaffold through a conformational restriction strategy. Structure-activity relationship (SAR) analysis resulted in the identification of several compounds with high potency in vitro and good metabolic stability in liver S9 fractions. Compounds 7c and 14b selected for further exploration in vivo demonstrated excellent pharmacokinetic profiles and exhibited significant inhibitory efficacy in SD rats upon oral dosing.
|
Inhibition of Lp-PLA2 in mouse plasma at 1 uM using 2-thio-PAF substrate after 10 mins
|
Mus musculus
|
99.0
%
|
|
Journal : J. Med. Chem.
Title : Discovery of a Novel Series of Imidazo[1,2-a]pyrimidine Derivatives as Potent and Orally Bioavailable Lipoprotein-Associated Phospholipase A2 Inhibitors.
Year : 2015
Volume : 58
Issue : 21
First Page : 8529
Last Page : 8541
Authors : Chen X, Xu W, Wang K, Mo M, Zhang W, Du L, Yuan X, Xu Y, Wang Y, Shen J.
Abstract : Inhibition of lipoprotein-associated phospholipase A2 (Lp-PLA2) has been suggested to be a promising therapeutic strategy for several inflammation-associated diseases, including atherosclerosis, Alzheimer's disease, and diabetic macular edema. Herein, we report the discovery of a novel series of Lp-PLA2 inhibitors constructed on an imidazo[1,2-a]pyrimidine scaffold through a conformational restriction strategy. Structure-activity relationship (SAR) analysis resulted in the identification of several compounds with high potency in vitro and good metabolic stability in liver S9 fractions. Compounds 7c and 14b selected for further exploration in vivo demonstrated excellent pharmacokinetic profiles and exhibited significant inhibitory efficacy in SD rats upon oral dosing.
|
Inhibition of Lp-PLA2 in Sprague-Dawley rat plasma at 10 nM using 2-thio-PAF substrate after 10 mins
|
Rattus norvegicus
|
84.0
%
|
|
Journal : J. Med. Chem.
Title : Discovery of a Novel Series of Imidazo[1,2-a]pyrimidine Derivatives as Potent and Orally Bioavailable Lipoprotein-Associated Phospholipase A2 Inhibitors.
Year : 2015
Volume : 58
Issue : 21
First Page : 8529
Last Page : 8541
Authors : Chen X, Xu W, Wang K, Mo M, Zhang W, Du L, Yuan X, Xu Y, Wang Y, Shen J.
Abstract : Inhibition of lipoprotein-associated phospholipase A2 (Lp-PLA2) has been suggested to be a promising therapeutic strategy for several inflammation-associated diseases, including atherosclerosis, Alzheimer's disease, and diabetic macular edema. Herein, we report the discovery of a novel series of Lp-PLA2 inhibitors constructed on an imidazo[1,2-a]pyrimidine scaffold through a conformational restriction strategy. Structure-activity relationship (SAR) analysis resulted in the identification of several compounds with high potency in vitro and good metabolic stability in liver S9 fractions. Compounds 7c and 14b selected for further exploration in vivo demonstrated excellent pharmacokinetic profiles and exhibited significant inhibitory efficacy in SD rats upon oral dosing.
|
Inhibition of Lp-PLA2 in Sprague-Dawley rat plasma at 100 nM using 2-thio-PAF substrate after 10 mins
|
Rattus norvegicus
|
98.0
%
|
|
Journal : J. Med. Chem.
Title : Discovery of a Novel Series of Imidazo[1,2-a]pyrimidine Derivatives as Potent and Orally Bioavailable Lipoprotein-Associated Phospholipase A2 Inhibitors.
Year : 2015
Volume : 58
Issue : 21
First Page : 8529
Last Page : 8541
Authors : Chen X, Xu W, Wang K, Mo M, Zhang W, Du L, Yuan X, Xu Y, Wang Y, Shen J.
Abstract : Inhibition of lipoprotein-associated phospholipase A2 (Lp-PLA2) has been suggested to be a promising therapeutic strategy for several inflammation-associated diseases, including atherosclerosis, Alzheimer's disease, and diabetic macular edema. Herein, we report the discovery of a novel series of Lp-PLA2 inhibitors constructed on an imidazo[1,2-a]pyrimidine scaffold through a conformational restriction strategy. Structure-activity relationship (SAR) analysis resulted in the identification of several compounds with high potency in vitro and good metabolic stability in liver S9 fractions. Compounds 7c and 14b selected for further exploration in vivo demonstrated excellent pharmacokinetic profiles and exhibited significant inhibitory efficacy in SD rats upon oral dosing.
|
Inhibition of Lp-PLA2 in human plasma at 10 nM using 2-thio-PAF substrate after 10 mins
|
Homo sapiens
|
93.0
%
|
|
Journal : J. Med. Chem.
Title : Discovery of a Novel Series of Imidazo[1,2-a]pyrimidine Derivatives as Potent and Orally Bioavailable Lipoprotein-Associated Phospholipase A2 Inhibitors.
Year : 2015
Volume : 58
Issue : 21
First Page : 8529
Last Page : 8541
Authors : Chen X, Xu W, Wang K, Mo M, Zhang W, Du L, Yuan X, Xu Y, Wang Y, Shen J.
Abstract : Inhibition of lipoprotein-associated phospholipase A2 (Lp-PLA2) has been suggested to be a promising therapeutic strategy for several inflammation-associated diseases, including atherosclerosis, Alzheimer's disease, and diabetic macular edema. Herein, we report the discovery of a novel series of Lp-PLA2 inhibitors constructed on an imidazo[1,2-a]pyrimidine scaffold through a conformational restriction strategy. Structure-activity relationship (SAR) analysis resulted in the identification of several compounds with high potency in vitro and good metabolic stability in liver S9 fractions. Compounds 7c and 14b selected for further exploration in vivo demonstrated excellent pharmacokinetic profiles and exhibited significant inhibitory efficacy in SD rats upon oral dosing.
|
Inhibition of Lp-PLA2 in human plasma at 100 nM using 2-thio-PAF substrate after 10 mins
|
Homo sapiens
|
100.0
%
|
|
Journal : J. Med. Chem.
Title : Discovery of a Novel Series of Imidazo[1,2-a]pyrimidine Derivatives as Potent and Orally Bioavailable Lipoprotein-Associated Phospholipase A2 Inhibitors.
Year : 2015
Volume : 58
Issue : 21
First Page : 8529
Last Page : 8541
Authors : Chen X, Xu W, Wang K, Mo M, Zhang W, Du L, Yuan X, Xu Y, Wang Y, Shen J.
Abstract : Inhibition of lipoprotein-associated phospholipase A2 (Lp-PLA2) has been suggested to be a promising therapeutic strategy for several inflammation-associated diseases, including atherosclerosis, Alzheimer's disease, and diabetic macular edema. Herein, we report the discovery of a novel series of Lp-PLA2 inhibitors constructed on an imidazo[1,2-a]pyrimidine scaffold through a conformational restriction strategy. Structure-activity relationship (SAR) analysis resulted in the identification of several compounds with high potency in vitro and good metabolic stability in liver S9 fractions. Compounds 7c and 14b selected for further exploration in vivo demonstrated excellent pharmacokinetic profiles and exhibited significant inhibitory efficacy in SD rats upon oral dosing.
|
Inhibition of recombinant human Lp-PLA2 using 2-thio-PAF substrate after 10 mins
|
Homo sapiens
|
0.7
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of a Novel Series of Imidazo[1,2-a]pyrimidine Derivatives as Potent and Orally Bioavailable Lipoprotein-Associated Phospholipase A2 Inhibitors.
Year : 2015
Volume : 58
Issue : 21
First Page : 8529
Last Page : 8541
Authors : Chen X, Xu W, Wang K, Mo M, Zhang W, Du L, Yuan X, Xu Y, Wang Y, Shen J.
Abstract : Inhibition of lipoprotein-associated phospholipase A2 (Lp-PLA2) has been suggested to be a promising therapeutic strategy for several inflammation-associated diseases, including atherosclerosis, Alzheimer's disease, and diabetic macular edema. Herein, we report the discovery of a novel series of Lp-PLA2 inhibitors constructed on an imidazo[1,2-a]pyrimidine scaffold through a conformational restriction strategy. Structure-activity relationship (SAR) analysis resulted in the identification of several compounds with high potency in vitro and good metabolic stability in liver S9 fractions. Compounds 7c and 14b selected for further exploration in vivo demonstrated excellent pharmacokinetic profiles and exhibited significant inhibitory efficacy in SD rats upon oral dosing.
|
Inhibition of recombinant human Lp-PLA2 at 100 nM using 2-thio-PAF substrate after 10 mins
|
Homo sapiens
|
92.0
%
|
|
Journal : J. Med. Chem.
Title : Discovery of a Novel Series of Imidazo[1,2-a]pyrimidine Derivatives as Potent and Orally Bioavailable Lipoprotein-Associated Phospholipase A2 Inhibitors.
Year : 2015
Volume : 58
Issue : 21
First Page : 8529
Last Page : 8541
Authors : Chen X, Xu W, Wang K, Mo M, Zhang W, Du L, Yuan X, Xu Y, Wang Y, Shen J.
Abstract : Inhibition of lipoprotein-associated phospholipase A2 (Lp-PLA2) has been suggested to be a promising therapeutic strategy for several inflammation-associated diseases, including atherosclerosis, Alzheimer's disease, and diabetic macular edema. Herein, we report the discovery of a novel series of Lp-PLA2 inhibitors constructed on an imidazo[1,2-a]pyrimidine scaffold through a conformational restriction strategy. Structure-activity relationship (SAR) analysis resulted in the identification of several compounds with high potency in vitro and good metabolic stability in liver S9 fractions. Compounds 7c and 14b selected for further exploration in vivo demonstrated excellent pharmacokinetic profiles and exhibited significant inhibitory efficacy in SD rats upon oral dosing.
|
Inhibition of recombinant human Lp-PLA2 at 10 nM using 2-thio-PAF substrate after 10 mins
|
Homo sapiens
|
88.0
%
|
|
Journal : J. Med. Chem.
Title : Discovery of a Novel Series of Imidazo[1,2-a]pyrimidine Derivatives as Potent and Orally Bioavailable Lipoprotein-Associated Phospholipase A2 Inhibitors.
Year : 2015
Volume : 58
Issue : 21
First Page : 8529
Last Page : 8541
Authors : Chen X, Xu W, Wang K, Mo M, Zhang W, Du L, Yuan X, Xu Y, Wang Y, Shen J.
Abstract : Inhibition of lipoprotein-associated phospholipase A2 (Lp-PLA2) has been suggested to be a promising therapeutic strategy for several inflammation-associated diseases, including atherosclerosis, Alzheimer's disease, and diabetic macular edema. Herein, we report the discovery of a novel series of Lp-PLA2 inhibitors constructed on an imidazo[1,2-a]pyrimidine scaffold through a conformational restriction strategy. Structure-activity relationship (SAR) analysis resulted in the identification of several compounds with high potency in vitro and good metabolic stability in liver S9 fractions. Compounds 7c and 14b selected for further exploration in vivo demonstrated excellent pharmacokinetic profiles and exhibited significant inhibitory efficacy in SD rats upon oral dosing.
|
Inhibition of recombinant human Lp-PLA2 using 2-thio-PAF as substrate measured for 10 mins by plate reader analysis
|
Homo sapiens
|
0.7
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of Potent and Orally Active Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Inhibitors as a Potential Therapy for Diabetic Macular Edema.
Year : 2016
Volume : 59
Issue : 6
First Page : 2674
Last Page : 2687
Authors : Chen X, Wang K, Xu W, Ma Q, Chen M, Du L, Mo M, Wang Y, Shen J.
Abstract : Lipoprotein-associated phospholipase A2 (Lp-PLA2) is considered to be a promising therapeutic target for several inflammation-associated diseases. Herein, we describe the discovery of a series of pyrimidone derivatives as Lp-PLA2 inhibitors. Systematic structural modifications led to the identification of several pyrimidone compounds with promising in vitro inhibitory potency and pharmacokinetic properties. Compound 14c, selected for in vivo evaluation, demonstrated decent pharmacokinetic profiles and robust inhibitory potency against Lp-PLA2 in Sprague-Dawley (SD) rats. Furthermore, 14c significantly inhibited retinal thickening in STZ-induced diabetic SD rats as a model of diabetic macular edema (DME) after oral dosing for 4 weeks. Taken together, these results suggested that 14c can serve as a valuable lead in the search for new Lp-PLA2 inhibitors for prevention and/or treatment of DME.
|
Inhibition of Lp-PLA2 in human plasma at 10 nM using 2-thio-PAF as substrate measured for 10 mins by plate reader analysis
|
Homo sapiens
|
94.0
%
|
|
Journal : J. Med. Chem.
Title : Discovery of Potent and Orally Active Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Inhibitors as a Potential Therapy for Diabetic Macular Edema.
Year : 2016
Volume : 59
Issue : 6
First Page : 2674
Last Page : 2687
Authors : Chen X, Wang K, Xu W, Ma Q, Chen M, Du L, Mo M, Wang Y, Shen J.
Abstract : Lipoprotein-associated phospholipase A2 (Lp-PLA2) is considered to be a promising therapeutic target for several inflammation-associated diseases. Herein, we describe the discovery of a series of pyrimidone derivatives as Lp-PLA2 inhibitors. Systematic structural modifications led to the identification of several pyrimidone compounds with promising in vitro inhibitory potency and pharmacokinetic properties. Compound 14c, selected for in vivo evaluation, demonstrated decent pharmacokinetic profiles and robust inhibitory potency against Lp-PLA2 in Sprague-Dawley (SD) rats. Furthermore, 14c significantly inhibited retinal thickening in STZ-induced diabetic SD rats as a model of diabetic macular edema (DME) after oral dosing for 4 weeks. Taken together, these results suggested that 14c can serve as a valuable lead in the search for new Lp-PLA2 inhibitors for prevention and/or treatment of DME.
|
Inhibition of Lp-PLA2 in human plasma at 1 nM using 2-thio-PAF as substrate measured for 10 mins by plate reader analysis
|
Homo sapiens
|
59.0
%
|
|
Journal : J. Med. Chem.
Title : Discovery of Potent and Orally Active Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Inhibitors as a Potential Therapy for Diabetic Macular Edema.
Year : 2016
Volume : 59
Issue : 6
First Page : 2674
Last Page : 2687
Authors : Chen X, Wang K, Xu W, Ma Q, Chen M, Du L, Mo M, Wang Y, Shen J.
Abstract : Lipoprotein-associated phospholipase A2 (Lp-PLA2) is considered to be a promising therapeutic target for several inflammation-associated diseases. Herein, we describe the discovery of a series of pyrimidone derivatives as Lp-PLA2 inhibitors. Systematic structural modifications led to the identification of several pyrimidone compounds with promising in vitro inhibitory potency and pharmacokinetic properties. Compound 14c, selected for in vivo evaluation, demonstrated decent pharmacokinetic profiles and robust inhibitory potency against Lp-PLA2 in Sprague-Dawley (SD) rats. Furthermore, 14c significantly inhibited retinal thickening in STZ-induced diabetic SD rats as a model of diabetic macular edema (DME) after oral dosing for 4 weeks. Taken together, these results suggested that 14c can serve as a valuable lead in the search for new Lp-PLA2 inhibitors for prevention and/or treatment of DME.
|
Inhibition of Lp-PLA2 in rat plasma at 100 nM using 2-thio-PAF as substrate measured for 10 mins by plate reader analysis
|
Rattus norvegicus
|
98.0
%
|
|
Journal : J. Med. Chem.
Title : Discovery of Potent and Orally Active Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Inhibitors as a Potential Therapy for Diabetic Macular Edema.
Year : 2016
Volume : 59
Issue : 6
First Page : 2674
Last Page : 2687
Authors : Chen X, Wang K, Xu W, Ma Q, Chen M, Du L, Mo M, Wang Y, Shen J.
Abstract : Lipoprotein-associated phospholipase A2 (Lp-PLA2) is considered to be a promising therapeutic target for several inflammation-associated diseases. Herein, we describe the discovery of a series of pyrimidone derivatives as Lp-PLA2 inhibitors. Systematic structural modifications led to the identification of several pyrimidone compounds with promising in vitro inhibitory potency and pharmacokinetic properties. Compound 14c, selected for in vivo evaluation, demonstrated decent pharmacokinetic profiles and robust inhibitory potency against Lp-PLA2 in Sprague-Dawley (SD) rats. Furthermore, 14c significantly inhibited retinal thickening in STZ-induced diabetic SD rats as a model of diabetic macular edema (DME) after oral dosing for 4 weeks. Taken together, these results suggested that 14c can serve as a valuable lead in the search for new Lp-PLA2 inhibitors for prevention and/or treatment of DME.
|
Inhibition of Lp-PLA2 in rat plasma at 10 nM using 2-thio-PAF as substrate measured for 10 mins by plate reader analysis
|
Rattus norvegicus
|
84.0
%
|
|
Journal : J. Med. Chem.
Title : Discovery of Potent and Orally Active Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Inhibitors as a Potential Therapy for Diabetic Macular Edema.
Year : 2016
Volume : 59
Issue : 6
First Page : 2674
Last Page : 2687
Authors : Chen X, Wang K, Xu W, Ma Q, Chen M, Du L, Mo M, Wang Y, Shen J.
Abstract : Lipoprotein-associated phospholipase A2 (Lp-PLA2) is considered to be a promising therapeutic target for several inflammation-associated diseases. Herein, we describe the discovery of a series of pyrimidone derivatives as Lp-PLA2 inhibitors. Systematic structural modifications led to the identification of several pyrimidone compounds with promising in vitro inhibitory potency and pharmacokinetic properties. Compound 14c, selected for in vivo evaluation, demonstrated decent pharmacokinetic profiles and robust inhibitory potency against Lp-PLA2 in Sprague-Dawley (SD) rats. Furthermore, 14c significantly inhibited retinal thickening in STZ-induced diabetic SD rats as a model of diabetic macular edema (DME) after oral dosing for 4 weeks. Taken together, these results suggested that 14c can serve as a valuable lead in the search for new Lp-PLA2 inhibitors for prevention and/or treatment of DME.
|
Inhibition of human recombinant Lp-PLA2 using 2-thio-PAF as substrate after 20 mins by CPM-based fluorescence assay
|
Homo sapiens
|
0.049
nM
|
|
Journal : J. Med. Chem.
Title : Exploitation of a Novel Binding Pocket in Human Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Discovered through X-ray Fragment Screening.
Year : 2016
Volume : 59
Issue : 11
First Page : 5356
Last Page : 5367
Authors : Woolford AJ, Pero JE, Aravapalli S, Berdini V, Coyle JE, Day PJ, Dodson AM, Grondin P, Holding FP, Lee LY, Li P, Manas ES, Marino J, Martin AC, McCleland BW, McMenamin RL, Murray CW, Neipp CE, Page LW, Patel VK, Potvain F, Rich S, Rivero RA, Smith K, Somers DO, Trottet L, Velagaleti R, Williams G, Xie R.
Abstract : Elevated levels of human lipoprotein-associated phospholipase A2 (Lp-PLA2) are associated with cardiovascular disease and dementia. A fragment screen was conducted against Lp-PLA2 in order to identify novel inhibitors. Multiple fragment hits were observed in different regions of the active site, including some hits that bound in a pocket created by movement of a protein side chain (approximately 13 Å from the catalytic residue Ser273). Using structure guided design, we optimized a fragment that bound in this pocket to generate a novel low nanomolar chemotype, which did not interact with the catalytic residues.
|
Inhibition of human recombinant PLA2-7B using 2-thio-PAF as substrate after 20 mins by CPM-based fluorescence assay
|
Homo sapiens
|
63.0
nM
|
|
Journal : J. Med. Chem.
Title : Exploitation of a Novel Binding Pocket in Human Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Discovered through X-ray Fragment Screening.
Year : 2016
Volume : 59
Issue : 11
First Page : 5356
Last Page : 5367
Authors : Woolford AJ, Pero JE, Aravapalli S, Berdini V, Coyle JE, Day PJ, Dodson AM, Grondin P, Holding FP, Lee LY, Li P, Manas ES, Marino J, Martin AC, McCleland BW, McMenamin RL, Murray CW, Neipp CE, Page LW, Patel VK, Potvain F, Rich S, Rivero RA, Smith K, Somers DO, Trottet L, Velagaleti R, Williams G, Xie R.
Abstract : Elevated levels of human lipoprotein-associated phospholipase A2 (Lp-PLA2) are associated with cardiovascular disease and dementia. A fragment screen was conducted against Lp-PLA2 in order to identify novel inhibitors. Multiple fragment hits were observed in different regions of the active site, including some hits that bound in a pocket created by movement of a protein side chain (approximately 13 Å from the catalytic residue Ser273). Using structure guided design, we optimized a fragment that bound in this pocket to generate a novel low nanomolar chemotype, which did not interact with the catalytic residues.
|
Inhibition of Lp-PLA2 in human whole plasma using 2-thio-PAF as substrate preincubated for 15 mins followed by substrate addition measured after 3 mins by CPM-based fluorescence assay
|
Homo sapiens
|
35.0
nM
|
|
Journal : J. Med. Chem.
Title : Exploitation of a Novel Binding Pocket in Human Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Discovered through X-ray Fragment Screening.
Year : 2016
Volume : 59
Issue : 11
First Page : 5356
Last Page : 5367
Authors : Woolford AJ, Pero JE, Aravapalli S, Berdini V, Coyle JE, Day PJ, Dodson AM, Grondin P, Holding FP, Lee LY, Li P, Manas ES, Marino J, Martin AC, McCleland BW, McMenamin RL, Murray CW, Neipp CE, Page LW, Patel VK, Potvain F, Rich S, Rivero RA, Smith K, Somers DO, Trottet L, Velagaleti R, Williams G, Xie R.
Abstract : Elevated levels of human lipoprotein-associated phospholipase A2 (Lp-PLA2) are associated with cardiovascular disease and dementia. A fragment screen was conducted against Lp-PLA2 in order to identify novel inhibitors. Multiple fragment hits were observed in different regions of the active site, including some hits that bound in a pocket created by movement of a protein side chain (approximately 13 Å from the catalytic residue Ser273). Using structure guided design, we optimized a fragment that bound in this pocket to generate a novel low nanomolar chemotype, which did not interact with the catalytic residues.
|
Binding affinity to human Lp-PLA2 by ITC assay
|
Homo sapiens
|
49.7
nM
|
|
Journal : J. Med. Chem.
Title : Structural and Thermodynamic Characterization of Protein-Ligand Interactions Formed between Lipoprotein-Associated Phospholipase A2 and Inhibitors.
Year : 2016
Volume : 59
Issue : 10
First Page : 5115
Last Page : 5120
Authors : Liu Q, Chen X, Chen W, Yuan X, Su H, Shen J, Xu Y.
Abstract : Lipoprotein-associated phospholipase A2 (Lp-PLA2) represents a promising therapeutic target for atherosclerosis and Alzheimer's disease. Here we reported the first crystal structures of Lp-PLA2 bound with reversible inhibitors and the thermodynamic characterization of complexes. High rigidity of Lp-PLA2 structure and similar binding modes of inhibitors with completely different scaffolds are revealed. It not only provides the molecular basis for inhibitory activity but also sheds light on the essential features of Lp-PLA2 recognition with reversible inhibitors.
|
Inhibition of Lp-PLA2 in whole human plasma pre-incubated for 15 mins before 2-thio-PAF substrate addition
|
Homo sapiens
|
0.035
nM
|
|
Journal : J Med Chem
Title : Fragment-Based Approach to the Development of an Orally Bioavailable Lactam Inhibitor of Lipoprotein-Associated Phospholipase A2 (Lp-PLA2).
Year : 2016
Volume : 59
Issue : 23
First Page : 10738
Last Page : 10749
Authors : Woolford AJ, Day PJ, Bénéton V, Berdini V, Coyle JE, Dudit Y, Grondin P, Huet P, Lee LY, Manas ES, McMenamin RL, Murray CW, Page LW, Patel VK, Potvain F, Rich SJ, Sang Y, Somers DO, Trottet L, Wan Z, Zhang X.
Abstract : Lp-PLA2 has been explored as a target for a number of inflammation associated diseases, including cardiovascular disease and dementia. This article describes the discovery of a new fragment derived chemotype that interacts with the active site of Lp-PLA2. The starting fragment hit was discovered through an X-ray fragment screen and showed no activity in the bioassay (IC50 > 1 mM). The fragment hit was optimized using a variety of structure-based drug design techniques, including virtual screening, fragment merging, and improvement of shape complementarity. A novel series of Lp-PLA2 inhibitors was generated with low lipophilicity and a promising pharmacokinetic profile.
|
Inhibition of recombinant human Lp-PLA2 incubated for 20 mins by Thio-PAF assay
|
Homo sapiens
|
0.049
nM
|
|
Journal : J Med Chem
Title : Fragment-Based Approach to the Development of an Orally Bioavailable Lactam Inhibitor of Lipoprotein-Associated Phospholipase A2 (Lp-PLA2).
Year : 2016
Volume : 59
Issue : 23
First Page : 10738
Last Page : 10749
Authors : Woolford AJ, Day PJ, Bénéton V, Berdini V, Coyle JE, Dudit Y, Grondin P, Huet P, Lee LY, Manas ES, McMenamin RL, Murray CW, Page LW, Patel VK, Potvain F, Rich SJ, Sang Y, Somers DO, Trottet L, Wan Z, Zhang X.
Abstract : Lp-PLA2 has been explored as a target for a number of inflammation associated diseases, including cardiovascular disease and dementia. This article describes the discovery of a new fragment derived chemotype that interacts with the active site of Lp-PLA2. The starting fragment hit was discovered through an X-ray fragment screen and showed no activity in the bioassay (IC50 > 1 mM). The fragment hit was optimized using a variety of structure-based drug design techniques, including virtual screening, fragment merging, and improvement of shape complementarity. A novel series of Lp-PLA2 inhibitors was generated with low lipophilicity and a promising pharmacokinetic profile.
|
Inhibition of recombinant human Lp-PLA2 pre-incubated for 30 mins before PED6 fluorogenic substrate
|
Homo sapiens
|
0.049
nM
|
|
Journal : J Med Chem
Title : Fragment-Based Approach to the Development of an Orally Bioavailable Lactam Inhibitor of Lipoprotein-Associated Phospholipase A2 (Lp-PLA2).
Year : 2016
Volume : 59
Issue : 23
First Page : 10738
Last Page : 10749
Authors : Woolford AJ, Day PJ, Bénéton V, Berdini V, Coyle JE, Dudit Y, Grondin P, Huet P, Lee LY, Manas ES, McMenamin RL, Murray CW, Page LW, Patel VK, Potvain F, Rich SJ, Sang Y, Somers DO, Trottet L, Wan Z, Zhang X.
Abstract : Lp-PLA2 has been explored as a target for a number of inflammation associated diseases, including cardiovascular disease and dementia. This article describes the discovery of a new fragment derived chemotype that interacts with the active site of Lp-PLA2. The starting fragment hit was discovered through an X-ray fragment screen and showed no activity in the bioassay (IC50 > 1 mM). The fragment hit was optimized using a variety of structure-based drug design techniques, including virtual screening, fragment merging, and improvement of shape complementarity. A novel series of Lp-PLA2 inhibitors was generated with low lipophilicity and a promising pharmacokinetic profile.
|
Inhibition of recombinant human PLA2-VIIB by Thio-PAF assay
|
Homo sapiens
|
63.0
nM
|
|
Journal : J Med Chem
Title : Fragment-Based Approach to the Development of an Orally Bioavailable Lactam Inhibitor of Lipoprotein-Associated Phospholipase A2 (Lp-PLA2).
Year : 2016
Volume : 59
Issue : 23
First Page : 10738
Last Page : 10749
Authors : Woolford AJ, Day PJ, Bénéton V, Berdini V, Coyle JE, Dudit Y, Grondin P, Huet P, Lee LY, Manas ES, McMenamin RL, Murray CW, Page LW, Patel VK, Potvain F, Rich SJ, Sang Y, Somers DO, Trottet L, Wan Z, Zhang X.
Abstract : Lp-PLA2 has been explored as a target for a number of inflammation associated diseases, including cardiovascular disease and dementia. This article describes the discovery of a new fragment derived chemotype that interacts with the active site of Lp-PLA2. The starting fragment hit was discovered through an X-ray fragment screen and showed no activity in the bioassay (IC50 > 1 mM). The fragment hit was optimized using a variety of structure-based drug design techniques, including virtual screening, fragment merging, and improvement of shape complementarity. A novel series of Lp-PLA2 inhibitors was generated with low lipophilicity and a promising pharmacokinetic profile.
|
Inhibition of human recombinant LpPLA2
|
Homo sapiens
|
0.0631
nM
|
|
Journal : ACS Med Chem Lett
Title : Investigation of a Bicyclo[1.1.1]pentane as a Phenyl Replacement within an LpPLA2 Inhibitor.
Year : 2017
Volume : 8
Issue : 1
First Page : 43
Last Page : 48
Authors : Measom ND, Down KD, Hirst DJ, Jamieson C, Manas ES, Patel VK, Somers DO.
Abstract : We describe the incorporation of a bicyclo[1.1.1]pentane moiety within two known LpPLA2 inhibitors to act as bioisosteric phenyl replacements. An efficient synthesis to the target compounds was enabled with a dichlorocarbene insertion into a bicyclo[1.1.0]butane system being the key transformation. Potency, physicochemical, and X-ray crystallographic data were obtained to compare the known inhibitors to their bioisosteric counterparts, which showed the isostere was well tolerated and positively impacted on the physicochemical profile.
|
Inhibition of Lp-PLA2 in rat plasma at 250 nM using 2-thio-PAF as substrate preincubated for 30 min followed by substrate addition measured every minute for 10 mins by DNTB reagent based assay by DNTB reagent based assay relative to control
|
Rattus norvegicus
|
97.0
%
|
|
Journal : J Med Chem
Title : Structure-Guided Discovery of Novel, Potent, and Orally Bioavailable Inhibitors of Lipoprotein-Associated Phospholipase A2.
Year : 2017
Volume : 60
Issue : 24
First Page : 10231
Last Page : 10244
Authors : Liu Q, Huang F, Yuan X, Wang K, Zou Y, Shen J, Xu Y.
Abstract : Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a promising therapeutic target for atherosclerosis, Alzheimer's disease, and diabetic macular edema. Here we report the identification of novel sulfonamide scaffold Lp-PLA2 inhibitors derived from a relatively weak fragment. Similarity searching on this fragment followed by molecular docking leads to the discovery of a micromolar inhibitor with a 300-fold potency improvement. Subsequently, by the application of a structure-guided design strategy, a successful hit-to-lead optimization was achieved and a number of Lp-PLA2 inhibitors with single-digit nanomolar potency were obtained. After preliminary evaluation of the properties of drug-likeness in vitro and in vivo, compound 37 stands out from this congeneric series of inhibitors for good inhibitory activity and favorable oral bioavailability in male Sprague-Dawley rats, providing a quality candidate for further development. The present study thus clearly demonstrates the power and advantage of integrally employing fragment screening, crystal structures determination, virtual screening, and medicinal chemistry in an efficient lead discovery project, providing a good example for structure-based drug design.
|
Inhibition of Lp-PLA2 in human plasma at 250 nM using 2-thio-PAF as substrate preincubated for 30 min followed by substrate addition measured every minute for 10 mins by DNTB reagent based assay relative to control
|
Homo sapiens
|
100.0
%
|
|
Journal : J Med Chem
Title : Structure-Guided Discovery of Novel, Potent, and Orally Bioavailable Inhibitors of Lipoprotein-Associated Phospholipase A2.
Year : 2017
Volume : 60
Issue : 24
First Page : 10231
Last Page : 10244
Authors : Liu Q, Huang F, Yuan X, Wang K, Zou Y, Shen J, Xu Y.
Abstract : Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a promising therapeutic target for atherosclerosis, Alzheimer's disease, and diabetic macular edema. Here we report the identification of novel sulfonamide scaffold Lp-PLA2 inhibitors derived from a relatively weak fragment. Similarity searching on this fragment followed by molecular docking leads to the discovery of a micromolar inhibitor with a 300-fold potency improvement. Subsequently, by the application of a structure-guided design strategy, a successful hit-to-lead optimization was achieved and a number of Lp-PLA2 inhibitors with single-digit nanomolar potency were obtained. After preliminary evaluation of the properties of drug-likeness in vitro and in vivo, compound 37 stands out from this congeneric series of inhibitors for good inhibitory activity and favorable oral bioavailability in male Sprague-Dawley rats, providing a quality candidate for further development. The present study thus clearly demonstrates the power and advantage of integrally employing fragment screening, crystal structures determination, virtual screening, and medicinal chemistry in an efficient lead discovery project, providing a good example for structure-based drug design.
|
Inhibition of human recombinant GST-tagged Lp-PLA2 (47 to 429 residues) expressed in Escherichia coli Rosetta(DE3) pLysS using 2-thio-PAF as substrate preincubated for 30 min followed by substrate addition measured every minute for 10 mins by DNTB reagent based assay
|
Homo sapiens
|
0.6
nM
|
|
Journal : J Med Chem
Title : Structure-Guided Discovery of Novel, Potent, and Orally Bioavailable Inhibitors of Lipoprotein-Associated Phospholipase A2.
Year : 2017
Volume : 60
Issue : 24
First Page : 10231
Last Page : 10244
Authors : Liu Q, Huang F, Yuan X, Wang K, Zou Y, Shen J, Xu Y.
Abstract : Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a promising therapeutic target for atherosclerosis, Alzheimer's disease, and diabetic macular edema. Here we report the identification of novel sulfonamide scaffold Lp-PLA2 inhibitors derived from a relatively weak fragment. Similarity searching on this fragment followed by molecular docking leads to the discovery of a micromolar inhibitor with a 300-fold potency improvement. Subsequently, by the application of a structure-guided design strategy, a successful hit-to-lead optimization was achieved and a number of Lp-PLA2 inhibitors with single-digit nanomolar potency were obtained. After preliminary evaluation of the properties of drug-likeness in vitro and in vivo, compound 37 stands out from this congeneric series of inhibitors for good inhibitory activity and favorable oral bioavailability in male Sprague-Dawley rats, providing a quality candidate for further development. The present study thus clearly demonstrates the power and advantage of integrally employing fragment screening, crystal structures determination, virtual screening, and medicinal chemistry in an efficient lead discovery project, providing a good example for structure-based drug design.
|
Inhibition of Lp-PLA2 in human plasma at 50 nM using 2-thio-PAF as substrate preincubated for 30 min followed by substrate addition measured every minute for 10 mins by DNTB reagent based assay relative to control
|
Homo sapiens
|
93.0
%
|
|
Journal : J Med Chem
Title : Structure-Guided Discovery of Novel, Potent, and Orally Bioavailable Inhibitors of Lipoprotein-Associated Phospholipase A2.
Year : 2017
Volume : 60
Issue : 24
First Page : 10231
Last Page : 10244
Authors : Liu Q, Huang F, Yuan X, Wang K, Zou Y, Shen J, Xu Y.
Abstract : Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a promising therapeutic target for atherosclerosis, Alzheimer's disease, and diabetic macular edema. Here we report the identification of novel sulfonamide scaffold Lp-PLA2 inhibitors derived from a relatively weak fragment. Similarity searching on this fragment followed by molecular docking leads to the discovery of a micromolar inhibitor with a 300-fold potency improvement. Subsequently, by the application of a structure-guided design strategy, a successful hit-to-lead optimization was achieved and a number of Lp-PLA2 inhibitors with single-digit nanomolar potency were obtained. After preliminary evaluation of the properties of drug-likeness in vitro and in vivo, compound 37 stands out from this congeneric series of inhibitors for good inhibitory activity and favorable oral bioavailability in male Sprague-Dawley rats, providing a quality candidate for further development. The present study thus clearly demonstrates the power and advantage of integrally employing fragment screening, crystal structures determination, virtual screening, and medicinal chemistry in an efficient lead discovery project, providing a good example for structure-based drug design.
|
Inhibition of Lp-PLA2 in rat plasma at 50 nM using 2-thio-PAF as substrate preincubated for 30 min followed by substrate addition measured every minute for 10 mins by DNTB reagent based assay relative to control
|
Rattus norvegicus
|
98.0
%
|
|
Journal : J Med Chem
Title : Structure-Guided Discovery of Novel, Potent, and Orally Bioavailable Inhibitors of Lipoprotein-Associated Phospholipase A2.
Year : 2017
Volume : 60
Issue : 24
First Page : 10231
Last Page : 10244
Authors : Liu Q, Huang F, Yuan X, Wang K, Zou Y, Shen J, Xu Y.
Abstract : Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a promising therapeutic target for atherosclerosis, Alzheimer's disease, and diabetic macular edema. Here we report the identification of novel sulfonamide scaffold Lp-PLA2 inhibitors derived from a relatively weak fragment. Similarity searching on this fragment followed by molecular docking leads to the discovery of a micromolar inhibitor with a 300-fold potency improvement. Subsequently, by the application of a structure-guided design strategy, a successful hit-to-lead optimization was achieved and a number of Lp-PLA2 inhibitors with single-digit nanomolar potency were obtained. After preliminary evaluation of the properties of drug-likeness in vitro and in vivo, compound 37 stands out from this congeneric series of inhibitors for good inhibitory activity and favorable oral bioavailability in male Sprague-Dawley rats, providing a quality candidate for further development. The present study thus clearly demonstrates the power and advantage of integrally employing fragment screening, crystal structures determination, virtual screening, and medicinal chemistry in an efficient lead discovery project, providing a good example for structure-based drug design.
|
Inhibition of Lp-PLA2 in human plasma LDL fractions using 2-thio platelet-activating factor as substrate by TMB dye based spectrophotometry
|
Homo sapiens
|
0.1
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Regioselectivity of thiouracil alkylation: Application to optimization of Darapladib synthesis.
Year : 2018
Volume : 28
Issue : 4
First Page : 787
Last Page : 792
Authors : Guibbal F, Bénard S, Patché J, Meneyrol V, Couprie J, Yong-Sang J, Meilhac O, Jestin E.
Abstract : Darapladib is one of the most potent Lp-PLA2 (Lipoprotein-associated phospholipase A2) inhibitor with an IC50 of 0.25 nM. We demonstrate that a crucial step of Darapladib synthesis was not correctly described in the literature, leading to the production of wrong regioisomers. Moreover we show that the inhibitory activity is directly linked to the position on N1 since compounds bearing alkylation on different sites have potentially less interaction within the active site of Lp-PLA2.
|
Inhibition of human Lp-PLA2
|
Homo sapiens
|
0.25
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Regioselectivity of thiouracil alkylation: Application to optimization of Darapladib synthesis.
Year : 2018
Volume : 28
Issue : 4
First Page : 787
Last Page : 792
Authors : Guibbal F, Bénard S, Patché J, Meneyrol V, Couprie J, Yong-Sang J, Meilhac O, Jestin E.
Abstract : Darapladib is one of the most potent Lp-PLA2 (Lipoprotein-associated phospholipase A2) inhibitor with an IC50 of 0.25 nM. We demonstrate that a crucial step of Darapladib synthesis was not correctly described in the literature, leading to the production of wrong regioisomers. Moreover we show that the inhibitory activity is directly linked to the position on N1 since compounds bearing alkylation on different sites have potentially less interaction within the active site of Lp-PLA2.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
0.57
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
15.33
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
17.58
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.38
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.39
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.39
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.38
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
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Inhibition of recombinant human Lp-PLA2 (47 to 429 residues) expressed in Escherichia coli RosettaTM2 (DE3) pLysS
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Homo sapiens
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0.7
nM
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Journal : J Med Chem
Title : Identification of Highly Selective Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Inhibitors by a Covalent Fragment-Based Approach.
Year : 2020
Volume : 63
Issue : 13
First Page : 7052
Last Page : 7065
Authors : Huang F, Hu H, Wang K, Peng C, Xu W, Zhang Y, Gao J, Liu Y, Zhou H, Huang R, Li M, Shen J, Xu Y.
Abstract : Covalent ligands are of great interest as therapeutic drugs or biochemical tools. Here, we reported the discovery of highly selective and irreversible inhibitors of lipoprotein-associated phospholipase A2 (Lp-PLA2) using a covalent fragment-based approach. The crystal structure of Lp-PLA2 in complex with a covalent fragment not only reveals the covalent reaction mechanism but also provides a good starting point to design compound 8, which has a more than 130,000-fold and 3900-fold increase in potency and selectivity, respectively, compared to those of the covalent fragment. Furthermore, fluorescent probes with high selectivity and sensitivity are developed to characterize Lp-PLA2 and its enzymatic activity in vitro or even in living cells in a way more convenient than immunoblotting tests or immunofluorescence imaging. Overall, we provide a paradigm for application of the covalent fragment-based strategy in covalent ligand discovery and the advantage of enol-cyclocarbamate as a new warhead in designing covalent inhibitors of serine hydrolases.
