The Experts below are selected from a list of 294 Experts worldwide ranked by ideXlab platform
Samuel Chackalamannil - One of the best experts on this subject based on the ideXlab platform.
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Himbacine-Derived Thrombin Receptor Antagonists: C7-Spirocyclic Analogues of Vorapaxar
ACS medicinal chemistry letters, 2014Co-Authors: Mariappan V. Chelliah, Samuel Chackalamannil, Keith Eagen, William J. Greenlee, Hsingan Tsai, Ho-sam Ahn, Xia Yan, Stan Kurowski, Zhuyan Guo, George BoykowAbstract:We have synthesized several C7-spirocyclic analogues of vorapaxar and evaluated their in vitro activities against PAR-1 receptor. Some of these analogues showed activities and rat plasma levels comparable to vorapaxar. Compound 5c from this series showed excellent PAR-1 activity (Ki = 5.1 nM). We also present a model of these spirocyclic compounds docked to the PAR-1 receptor based on the X-ray crystal structure of vorapaxar bound to PAR-1 receptor. This model explains some of the structure–activity relationships in this series.
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Discovery of nor-seco Himbacine analogs as thrombin receptor antagonists.
Bioorganic & medicinal chemistry letters, 2012Co-Authors: Mariappan V. Chelliah, Samuel Chackalamannil, Keith Eagen, William J. Greenlee, Ho-sam Ahn, Yunsheng Hsieh, Xia Yan, George Boykow, Jacqueline Agans-fantuzzi, Matthew BryantAbstract:Discovery of a novel nor-seco Himbacine analog as potent thrombin receptor (PAR-1) antagonist is described. Despite low plasma level, these new analogs showed excellent ex vivo efficacy in the monkey platelet aggregation assay. A potent hydroxy metabolite generated in vivo was identified as the agent responsible for the ex vivo efficacy. Following this discovery, the metabolite series was optimized to obtain analogs that showed very good ex vivo efficacy along with excellent pharmacokinetic profile in c. monkey.
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Discovery of a vorapaxar analog with increased aqueous solubility.
Bioorganic & medicinal chemistry letters, 2010Co-Authors: Xia Yan, Samuel Chackalamannil, William J. Greenlee, Yuguang Wang, Ho-sam Ahn, Yuriko Root, Jesse K. Wong, Jianshe Kong, George BoykowAbstract:An analog of the thrombin receptor antagonist vorapaxar (SCH 530348) with increased aqueous solubility, compound 9c (SCH 602539), was discovered through incorporation of polar substituents on the pyridine ring of the Himbacine-derived lead series. This analog retained the excellent potency, pharmacokinetic and safety properties of vorapaxar while increasing the aqueous solubility by 20-fold. Also presented are in vivo evaluations of this compound in a cynomolgus monkey platelet aggregation assay and in a Folts model of thrombosis in anesthetized monkeys.
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discovery of a novel orally active Himbacine based thrombin receptor antagonist sch 530348 with potent antiplatelet activity
Journal of Medicinal Chemistry, 2008Co-Authors: Samuel Chackalamannil, William J. Greenlee, Yuguang Wang, Yunsheng Hsieh, George Boykow, Zhiyong Hu, Jairam Palamanda, Jacqueline Agansfantuzzi, Stan Kurowski, Michael P GrazianoAbstract:The discovery of an exceptionally potent series of thrombin receptor (PAR-1) antagonists based on the natural product Himbacine is described. Optimization of this series has led to the discovery of 4 (SCH 530348), a potent, oral antiplatelet agent that is currently undergoing Phase-III clinical trials for acute coronary syndrome (unstable angina/non-ST segment elevation myocardial infarction) and secondary prevention of cardiovascular events in high-risk patients.
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Heterotricyclic Himbacine analogs as potent, orally active thrombin receptor (protease activated receptor-1) antagonists.
Journal of medicinal chemistry, 2007Co-Authors: Chelliah Mariappan, Yan Xia, Samuel Chackalamannil, Keith Eagen, William J. Greenlee, Ho-sam Ahn, Martin C. Clasby, Xiaobang Gao, Jacqueline Agans-fantuzzi, George BoykowAbstract:Pursuing our earlier efforts in the Himbacine-based thrombin receptor antagonist area, we have synthesized a series of compounds that incorporate heteroatoms in the C-ring of the tricyclic motif. This effort has resulted in the identification of several potent heterocyclic analogs with excellent affinity for the thrombin receptor. Several of these compounds demonstrated robust inhibition of platelet aggregation in an ex vivo model in cynomolgus monkeys following oral administration. A detailed profile of 28b, a benchmark compound in this series, with a Ki of 4.3 nM, is presented.
George Boykow - One of the best experts on this subject based on the ideXlab platform.
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Himbacine-Derived Thrombin Receptor Antagonists: C7-Spirocyclic Analogues of Vorapaxar
ACS medicinal chemistry letters, 2014Co-Authors: Mariappan V. Chelliah, Samuel Chackalamannil, Keith Eagen, William J. Greenlee, Hsingan Tsai, Ho-sam Ahn, Xia Yan, Stan Kurowski, Zhuyan Guo, George BoykowAbstract:We have synthesized several C7-spirocyclic analogues of vorapaxar and evaluated their in vitro activities against PAR-1 receptor. Some of these analogues showed activities and rat plasma levels comparable to vorapaxar. Compound 5c from this series showed excellent PAR-1 activity (Ki = 5.1 nM). We also present a model of these spirocyclic compounds docked to the PAR-1 receptor based on the X-ray crystal structure of vorapaxar bound to PAR-1 receptor. This model explains some of the structure–activity relationships in this series.
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Discovery of nor-seco Himbacine analogs as thrombin receptor antagonists.
Bioorganic & medicinal chemistry letters, 2012Co-Authors: Mariappan V. Chelliah, Samuel Chackalamannil, Keith Eagen, William J. Greenlee, Ho-sam Ahn, Yunsheng Hsieh, Xia Yan, George Boykow, Jacqueline Agans-fantuzzi, Matthew BryantAbstract:Discovery of a novel nor-seco Himbacine analog as potent thrombin receptor (PAR-1) antagonist is described. Despite low plasma level, these new analogs showed excellent ex vivo efficacy in the monkey platelet aggregation assay. A potent hydroxy metabolite generated in vivo was identified as the agent responsible for the ex vivo efficacy. Following this discovery, the metabolite series was optimized to obtain analogs that showed very good ex vivo efficacy along with excellent pharmacokinetic profile in c. monkey.
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Discovery of a vorapaxar analog with increased aqueous solubility.
Bioorganic & medicinal chemistry letters, 2010Co-Authors: Xia Yan, Samuel Chackalamannil, William J. Greenlee, Yuguang Wang, Ho-sam Ahn, Yuriko Root, Jesse K. Wong, Jianshe Kong, George BoykowAbstract:An analog of the thrombin receptor antagonist vorapaxar (SCH 530348) with increased aqueous solubility, compound 9c (SCH 602539), was discovered through incorporation of polar substituents on the pyridine ring of the Himbacine-derived lead series. This analog retained the excellent potency, pharmacokinetic and safety properties of vorapaxar while increasing the aqueous solubility by 20-fold. Also presented are in vivo evaluations of this compound in a cynomolgus monkey platelet aggregation assay and in a Folts model of thrombosis in anesthetized monkeys.
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discovery of a novel orally active Himbacine based thrombin receptor antagonist sch 530348 with potent antiplatelet activity
Journal of Medicinal Chemistry, 2008Co-Authors: Samuel Chackalamannil, William J. Greenlee, Yuguang Wang, Yunsheng Hsieh, George Boykow, Zhiyong Hu, Jairam Palamanda, Jacqueline Agansfantuzzi, Stan Kurowski, Michael P GrazianoAbstract:The discovery of an exceptionally potent series of thrombin receptor (PAR-1) antagonists based on the natural product Himbacine is described. Optimization of this series has led to the discovery of 4 (SCH 530348), a potent, oral antiplatelet agent that is currently undergoing Phase-III clinical trials for acute coronary syndrome (unstable angina/non-ST segment elevation myocardial infarction) and secondary prevention of cardiovascular events in high-risk patients.
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Heterotricyclic Himbacine analogs as potent, orally active thrombin receptor (protease activated receptor-1) antagonists.
Journal of medicinal chemistry, 2007Co-Authors: Chelliah Mariappan, Yan Xia, Samuel Chackalamannil, Keith Eagen, William J. Greenlee, Ho-sam Ahn, Martin C. Clasby, Xiaobang Gao, Jacqueline Agans-fantuzzi, George BoykowAbstract:Pursuing our earlier efforts in the Himbacine-based thrombin receptor antagonist area, we have synthesized a series of compounds that incorporate heteroatoms in the C-ring of the tricyclic motif. This effort has resulted in the identification of several potent heterocyclic analogs with excellent affinity for the thrombin receptor. Several of these compounds demonstrated robust inhibition of platelet aggregation in an ex vivo model in cynomolgus monkeys following oral administration. A detailed profile of 28b, a benchmark compound in this series, with a Ki of 4.3 nM, is presented.
William J. Greenlee - One of the best experts on this subject based on the ideXlab platform.
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Himbacine-Derived Thrombin Receptor Antagonists: C7-Spirocyclic Analogues of Vorapaxar
ACS medicinal chemistry letters, 2014Co-Authors: Mariappan V. Chelliah, Samuel Chackalamannil, Keith Eagen, William J. Greenlee, Hsingan Tsai, Ho-sam Ahn, Xia Yan, Stan Kurowski, Zhuyan Guo, George BoykowAbstract:We have synthesized several C7-spirocyclic analogues of vorapaxar and evaluated their in vitro activities against PAR-1 receptor. Some of these analogues showed activities and rat plasma levels comparable to vorapaxar. Compound 5c from this series showed excellent PAR-1 activity (Ki = 5.1 nM). We also present a model of these spirocyclic compounds docked to the PAR-1 receptor based on the X-ray crystal structure of vorapaxar bound to PAR-1 receptor. This model explains some of the structure–activity relationships in this series.
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Discovery of nor-seco Himbacine analogs as thrombin receptor antagonists.
Bioorganic & medicinal chemistry letters, 2012Co-Authors: Mariappan V. Chelliah, Samuel Chackalamannil, Keith Eagen, William J. Greenlee, Ho-sam Ahn, Yunsheng Hsieh, Xia Yan, George Boykow, Jacqueline Agans-fantuzzi, Matthew BryantAbstract:Discovery of a novel nor-seco Himbacine analog as potent thrombin receptor (PAR-1) antagonist is described. Despite low plasma level, these new analogs showed excellent ex vivo efficacy in the monkey platelet aggregation assay. A potent hydroxy metabolite generated in vivo was identified as the agent responsible for the ex vivo efficacy. Following this discovery, the metabolite series was optimized to obtain analogs that showed very good ex vivo efficacy along with excellent pharmacokinetic profile in c. monkey.
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Discovery of a vorapaxar analog with increased aqueous solubility.
Bioorganic & medicinal chemistry letters, 2010Co-Authors: Xia Yan, Samuel Chackalamannil, William J. Greenlee, Yuguang Wang, Ho-sam Ahn, Yuriko Root, Jesse K. Wong, Jianshe Kong, George BoykowAbstract:An analog of the thrombin receptor antagonist vorapaxar (SCH 530348) with increased aqueous solubility, compound 9c (SCH 602539), was discovered through incorporation of polar substituents on the pyridine ring of the Himbacine-derived lead series. This analog retained the excellent potency, pharmacokinetic and safety properties of vorapaxar while increasing the aqueous solubility by 20-fold. Also presented are in vivo evaluations of this compound in a cynomolgus monkey platelet aggregation assay and in a Folts model of thrombosis in anesthetized monkeys.
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discovery of a novel orally active Himbacine based thrombin receptor antagonist sch 530348 with potent antiplatelet activity
Journal of Medicinal Chemistry, 2008Co-Authors: Samuel Chackalamannil, William J. Greenlee, Yuguang Wang, Yunsheng Hsieh, George Boykow, Zhiyong Hu, Jairam Palamanda, Jacqueline Agansfantuzzi, Stan Kurowski, Michael P GrazianoAbstract:The discovery of an exceptionally potent series of thrombin receptor (PAR-1) antagonists based on the natural product Himbacine is described. Optimization of this series has led to the discovery of 4 (SCH 530348), a potent, oral antiplatelet agent that is currently undergoing Phase-III clinical trials for acute coronary syndrome (unstable angina/non-ST segment elevation myocardial infarction) and secondary prevention of cardiovascular events in high-risk patients.
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Heterotricyclic Himbacine analogs as potent, orally active thrombin receptor (protease activated receptor-1) antagonists.
Journal of medicinal chemistry, 2007Co-Authors: Chelliah Mariappan, Yan Xia, Samuel Chackalamannil, Keith Eagen, William J. Greenlee, Ho-sam Ahn, Martin C. Clasby, Xiaobang Gao, Jacqueline Agans-fantuzzi, George BoykowAbstract:Pursuing our earlier efforts in the Himbacine-based thrombin receptor antagonist area, we have synthesized a series of compounds that incorporate heteroatoms in the C-ring of the tricyclic motif. This effort has resulted in the identification of several potent heterocyclic analogs with excellent affinity for the thrombin receptor. Several of these compounds demonstrated robust inhibition of platelet aggregation in an ex vivo model in cynomolgus monkeys following oral administration. A detailed profile of 28b, a benchmark compound in this series, with a Ki of 4.3 nM, is presented.
Ho-sam Ahn - One of the best experts on this subject based on the ideXlab platform.
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Himbacine-Derived Thrombin Receptor Antagonists: C7-Spirocyclic Analogues of Vorapaxar
ACS medicinal chemistry letters, 2014Co-Authors: Mariappan V. Chelliah, Samuel Chackalamannil, Keith Eagen, William J. Greenlee, Hsingan Tsai, Ho-sam Ahn, Xia Yan, Stan Kurowski, Zhuyan Guo, George BoykowAbstract:We have synthesized several C7-spirocyclic analogues of vorapaxar and evaluated their in vitro activities against PAR-1 receptor. Some of these analogues showed activities and rat plasma levels comparable to vorapaxar. Compound 5c from this series showed excellent PAR-1 activity (Ki = 5.1 nM). We also present a model of these spirocyclic compounds docked to the PAR-1 receptor based on the X-ray crystal structure of vorapaxar bound to PAR-1 receptor. This model explains some of the structure–activity relationships in this series.
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Discovery of nor-seco Himbacine analogs as thrombin receptor antagonists.
Bioorganic & medicinal chemistry letters, 2012Co-Authors: Mariappan V. Chelliah, Samuel Chackalamannil, Keith Eagen, William J. Greenlee, Ho-sam Ahn, Yunsheng Hsieh, Xia Yan, George Boykow, Jacqueline Agans-fantuzzi, Matthew BryantAbstract:Discovery of a novel nor-seco Himbacine analog as potent thrombin receptor (PAR-1) antagonist is described. Despite low plasma level, these new analogs showed excellent ex vivo efficacy in the monkey platelet aggregation assay. A potent hydroxy metabolite generated in vivo was identified as the agent responsible for the ex vivo efficacy. Following this discovery, the metabolite series was optimized to obtain analogs that showed very good ex vivo efficacy along with excellent pharmacokinetic profile in c. monkey.
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Discovery of a vorapaxar analog with increased aqueous solubility.
Bioorganic & medicinal chemistry letters, 2010Co-Authors: Xia Yan, Samuel Chackalamannil, William J. Greenlee, Yuguang Wang, Ho-sam Ahn, Yuriko Root, Jesse K. Wong, Jianshe Kong, George BoykowAbstract:An analog of the thrombin receptor antagonist vorapaxar (SCH 530348) with increased aqueous solubility, compound 9c (SCH 602539), was discovered through incorporation of polar substituents on the pyridine ring of the Himbacine-derived lead series. This analog retained the excellent potency, pharmacokinetic and safety properties of vorapaxar while increasing the aqueous solubility by 20-fold. Also presented are in vivo evaluations of this compound in a cynomolgus monkey platelet aggregation assay and in a Folts model of thrombosis in anesthetized monkeys.
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Heterotricyclic Himbacine analogs as potent, orally active thrombin receptor (protease activated receptor-1) antagonists.
Journal of medicinal chemistry, 2007Co-Authors: Chelliah Mariappan, Yan Xia, Samuel Chackalamannil, Keith Eagen, William J. Greenlee, Ho-sam Ahn, Martin C. Clasby, Xiaobang Gao, Jacqueline Agans-fantuzzi, George BoykowAbstract:Pursuing our earlier efforts in the Himbacine-based thrombin receptor antagonist area, we have synthesized a series of compounds that incorporate heteroatoms in the C-ring of the tricyclic motif. This effort has resulted in the identification of several potent heterocyclic analogs with excellent affinity for the thrombin receptor. Several of these compounds demonstrated robust inhibition of platelet aggregation in an ex vivo model in cynomolgus monkeys following oral administration. A detailed profile of 28b, a benchmark compound in this series, with a Ki of 4.3 nM, is presented.
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Himbacine derived thrombin receptor (PAR-1) antagonists: SAR of the pyridine ring.
Bioorganic & medicinal chemistry letters, 2007Co-Authors: Yan Xia, Samuel Chackalamannil, Keith Eagen, William J. Greenlee, Hsingan Tsai, Ho-sam Ahn, Martin C. Clasby, Jacqueline Agans-fantuzzi, Dario Doller, George BoykowAbstract:The structure-activity relationship (SAR) of the vinyl pyridine region of Himbacine derived thrombin receptor (PAR-1) antagonists is described. A 2-vinylpyridyl ring substituted with an aryl or a heteroaryl group at the 5-position showed the best overall PAR-1 affinity and pharmacokinetic properties. One of the newly discovered analogs bearing a 5-(3-pyridyl) substituent showed excellent PAR-1 affinity (Ki = 22 nM) and oral activity with reduced ClogP and improved off-target selectivity compared to an earlier development candidate.
Yan Xia - One of the best experts on this subject based on the ideXlab platform.
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Heterotricyclic Himbacine analogs as potent, orally active thrombin receptor (protease activated receptor-1) antagonists.
Journal of medicinal chemistry, 2007Co-Authors: Chelliah Mariappan, Yan Xia, Samuel Chackalamannil, Keith Eagen, William J. Greenlee, Ho-sam Ahn, Martin C. Clasby, Xiaobang Gao, Jacqueline Agans-fantuzzi, George BoykowAbstract:Pursuing our earlier efforts in the Himbacine-based thrombin receptor antagonist area, we have synthesized a series of compounds that incorporate heteroatoms in the C-ring of the tricyclic motif. This effort has resulted in the identification of several potent heterocyclic analogs with excellent affinity for the thrombin receptor. Several of these compounds demonstrated robust inhibition of platelet aggregation in an ex vivo model in cynomolgus monkeys following oral administration. A detailed profile of 28b, a benchmark compound in this series, with a Ki of 4.3 nM, is presented.
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Himbacine derived thrombin receptor (PAR-1) antagonists: SAR of the pyridine ring.
Bioorganic & medicinal chemistry letters, 2007Co-Authors: Yan Xia, Samuel Chackalamannil, Keith Eagen, William J. Greenlee, Hsingan Tsai, Ho-sam Ahn, Martin C. Clasby, Jacqueline Agans-fantuzzi, Dario Doller, George BoykowAbstract:The structure-activity relationship (SAR) of the vinyl pyridine region of Himbacine derived thrombin receptor (PAR-1) antagonists is described. A 2-vinylpyridyl ring substituted with an aryl or a heteroaryl group at the 5-position showed the best overall PAR-1 affinity and pharmacokinetic properties. One of the newly discovered analogs bearing a 5-(3-pyridyl) substituent showed excellent PAR-1 affinity (Ki = 22 nM) and oral activity with reduced ClogP and improved off-target selectivity compared to an earlier development candidate.
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Himbacine derived thrombin receptor antagonists: discovery of a new tricyclic core.
Bioorganic & medicinal chemistry letters, 2007Co-Authors: Martin C. Clasby, Samuel Chackalamannil, Keith Eagen, William J. Greenlee, Hsingan Tsai, Dario Doller, Michael Czarniecki, Yan Lin, Jayaram R. Tagat, Yan XiaAbstract:The synthesis and biological activity of a novel series of thrombin receptor antagonists is described. This series of compounds showed excellent in vitro and in vivo potency. The most potent compound 40 had an IC50 of 7.6 nM and showed robust inhibition of platelet aggregation in a cynomolgus monkey model after oral administration.
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Himbacine derived thrombin receptor (PAR-1) antagonists: structure-activity relationship of the lactone ring.
Bioorganic & medicinal chemistry letters, 2006Co-Authors: Yan Xia, Samuel Chackalamannil, Tze-ming Chan, Michael F. Czarniecki, Doller Dario, Keith Eagen, William J. Greenlee, Hsingan Tsai, Yuguang Wang, Ho-sam AhnAbstract:Abstract The structure–activity relationship (SAR) of the lactone ring of Himbacine derived thrombin receptor (PAR-1) antagoinsts (e.g., 2 – 5 ) is described. The effect of the lactone carbonyl group on binding to PAR-1 is dependent on the substitution pattern of the pyridine ring. A stereoselective intramolecular Michael addition reaction to the vinyl pyridine group was observed for these pyridine analogs of Himbacine in basic conditions at elevated temperature.
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discovery of potent orally active thrombin receptor protease activated receptor 1 antagonists as novel antithrombotic agents
Journal of Medicinal Chemistry, 2005Co-Authors: Samuel Chackalamannil, Yan Xia, William J. Greenlee, Hsingan Tsai, Ho-sam Ahn, Martin C. Clasby, Dario Doller, Michael Czarniecki, Theodros Asberom, George BoykowAbstract:Structurally novel thrombin receptor (protease activated receptor 1, PAR-1) antagonists based on the natural product Himbacine are described. The prototypical PAR-1 antagonist 55 showed a Ki of 2.7 nM in the binding assay, making it the most potent PAR-1 antagonist reported. 55 was highly active in several functional assays, showed excellent oral bioavailability in rat and monkey models, and showed complete inhibition of agonist-induced ex vivo platelet aggregation in cynomolgus monkeys after oral administration.