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Martin S. Springer - One of the best experts on this subject based on the ideXlab platform.
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potent 1 3 4 trisubstituted pyrrolidine CCR5 Receptor antagonists effects of fused heterocycles on antiviral activity and pharmacokinetic properties
Bioorganic & Medicinal Chemistry Letters, 2005Co-Authors: Liping Wang, Christopher L. Lynch, Jeffrey J. Hale, Richard J. Budhu, Sander G. Mills, Malcolm Maccoss, Lorraine Malkowitz, Sandra L. Gould, Julie A. Demartino, Martin S. SpringerAbstract:A series of 1,3,4-trisubstituted pyrrolidine CCR5 Receptor antagonists containing a variety of fused heterocycles at the 4-position of the piperidine side chain has been discovered, which are orally bioavailable with potent anti-HIV activity.
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antagonists of human CCR5 Receptor containing 4 pyrazolyl piperidine side chains part 3 sar studies on the benzylpyrazole segment
Bioorganic & Medicinal Chemistry Letters, 2004Co-Authors: Min Shu, Sander G. Mills, Kevin T. Chapman, Lorraine Malkowitz, Martin S. Springer, Sandra L. Gould, Jennifer L Loebach, Kerry A Parker, Dongming Shen, Julie A. DemartinoAbstract:Extensive SAR studies in our benzylpyrazole series of CCR5 antagonists have shown that both lipophilic and hydrophilic substituents on the phenyl of the benzyl group increase antiviral potency. However, improvements in pharmacokinetic profiles were generally only observed with more lipophilic substitutions. 4-Biphenyl (51) performed the best in this regard. Highly lipophilic substituents impart undesirable ion channel activity to these CCR5 antagonists. Alkoxy substituents provide a good balance of antiviral activity, pharmacokinetic parameters, and selectivity. Compounds 42b and 42d, containing a 3,4-dimethoxy substituent, are considered the most promising improvements over parent compounds 9. They demonstrate improved antiviral activity while retaining good pharmacokinetic profile and selectivity.
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antagonists of human CCR5 Receptor containing 4 pyrazolyl piperidine side chains part 2 discovery of potent selective and orally bioavailable compounds
Bioorganic & Medicinal Chemistry Letters, 2004Co-Authors: Dongming Shen, Christopher L. Lynch, Jeffrey J. Hale, Sander G. Mills, Kevin T. Chapman, Lorraine Malkowitz, Christopher A Willoughby, Min Shu, Shrenik K Shah, Martin S. SpringerAbstract:Modifications of the alkyl acetic acid portion and the phenyl on pyrrolidine in our lead pyrazole compound 1 afforded the isopropyl compound 9. This compound is a potent CCR5 antagonist showing good in vitro antiviral activity against HIV-1, an excellent selectivity profile, and good oral bioavailability in three animal species. During this investigation, a new method for the preparation of α-(pyrrolidin-1-yl)-α,α-dialkyl acetic acid from a pyrrolidine and α-bromo-α,α-dialkyl acetic acid using silver triflate was discovered. This allowed us to prepare compounds such as 24 and 25 for the first time. A novel Pd-mediated N-dealkylation of α-(pyrrolidin-1-yl)acetic acid was also uncovered.
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antagonists of human CCR5 Receptor containing 4 pyrazolyl piperidine side chains part 1 discovery and sar study of 4 pyrazolylpiperidine side chains
Bioorganic & Medicinal Chemistry Letters, 2004Co-Authors: Dongming Shen, Sander G. Mills, Kevin T. Chapman, Lorraine Malkowitz, Martin S. Springer, Sandra L. Gould, Salvatore J. Siciliano, Julie A. Demartino, Min Shu, Gloria Y KweiAbstract:Replacement of the flexible connecting chains between the piperidine moiety and an aromatic group in previous CCR5 antagonists with heterocycles, such as pyrazole and isoxazole, provided potent CCR5 antagonists with excellent anti-HIV-1 activity in vitro. SAR studies revealed optimal placement of an unsubstituted nitrogen atom in the heterocycle to be meta to the bond connected to the 4-position of piperidine. Truncation of a benzyl group to a phenyl group afforded compounds with dramatically improved oral bioavailability, albeit with reduced activity.
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1,3,4-Trisubstituted pyrrolidine CCR5 Receptor antagonists. Part 4: synthesis of N-1 acidic functionality affording analogues with enhanced antiviral activity against HIV.
Bioorganic & medicinal chemistry letters, 2002Co-Authors: Christopher L. Lynch, Jeffrey J. Hale, Richard J. Budhu, Amy Gentry, Sander G. Mills, Kevin T. Chapman, Malcolm Maccoss, Lorraine Malkowitz, Martin S. Springer, Sandra L. GouldAbstract:A series of α-(pyrrolidin-1-yl)acetic acids is presented as selective and potent antivirals against HIV. Several of the pyrrolidine zwitterions demonstrated reasonable in vitro properties, enhanced antiviral activities and improved pharmacokinetic profiles over pyrrolidine 1.
Sander G. Mills - One of the best experts on this subject based on the ideXlab platform.
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potent 1 3 4 trisubstituted pyrrolidine CCR5 Receptor antagonists effects of fused heterocycles on antiviral activity and pharmacokinetic properties
Bioorganic & Medicinal Chemistry Letters, 2005Co-Authors: Liping Wang, Christopher L. Lynch, Jeffrey J. Hale, Richard J. Budhu, Sander G. Mills, Malcolm Maccoss, Lorraine Malkowitz, Sandra L. Gould, Julie A. Demartino, Martin S. SpringerAbstract:A series of 1,3,4-trisubstituted pyrrolidine CCR5 Receptor antagonists containing a variety of fused heterocycles at the 4-position of the piperidine side chain has been discovered, which are orally bioavailable with potent anti-HIV activity.
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antagonists of human CCR5 Receptor containing 4 pyrazolyl piperidine side chains part 3 sar studies on the benzylpyrazole segment
Bioorganic & Medicinal Chemistry Letters, 2004Co-Authors: Min Shu, Sander G. Mills, Kevin T. Chapman, Lorraine Malkowitz, Martin S. Springer, Sandra L. Gould, Jennifer L Loebach, Kerry A Parker, Dongming Shen, Julie A. DemartinoAbstract:Extensive SAR studies in our benzylpyrazole series of CCR5 antagonists have shown that both lipophilic and hydrophilic substituents on the phenyl of the benzyl group increase antiviral potency. However, improvements in pharmacokinetic profiles were generally only observed with more lipophilic substitutions. 4-Biphenyl (51) performed the best in this regard. Highly lipophilic substituents impart undesirable ion channel activity to these CCR5 antagonists. Alkoxy substituents provide a good balance of antiviral activity, pharmacokinetic parameters, and selectivity. Compounds 42b and 42d, containing a 3,4-dimethoxy substituent, are considered the most promising improvements over parent compounds 9. They demonstrate improved antiviral activity while retaining good pharmacokinetic profile and selectivity.
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antagonists of human CCR5 Receptor containing 4 pyrazolyl piperidine side chains part 2 discovery of potent selective and orally bioavailable compounds
Bioorganic & Medicinal Chemistry Letters, 2004Co-Authors: Dongming Shen, Christopher L. Lynch, Jeffrey J. Hale, Sander G. Mills, Kevin T. Chapman, Lorraine Malkowitz, Christopher A Willoughby, Min Shu, Shrenik K Shah, Martin S. SpringerAbstract:Modifications of the alkyl acetic acid portion and the phenyl on pyrrolidine in our lead pyrazole compound 1 afforded the isopropyl compound 9. This compound is a potent CCR5 antagonist showing good in vitro antiviral activity against HIV-1, an excellent selectivity profile, and good oral bioavailability in three animal species. During this investigation, a new method for the preparation of α-(pyrrolidin-1-yl)-α,α-dialkyl acetic acid from a pyrrolidine and α-bromo-α,α-dialkyl acetic acid using silver triflate was discovered. This allowed us to prepare compounds such as 24 and 25 for the first time. A novel Pd-mediated N-dealkylation of α-(pyrrolidin-1-yl)acetic acid was also uncovered.
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antagonists of human CCR5 Receptor containing 4 pyrazolyl piperidine side chains part 1 discovery and sar study of 4 pyrazolylpiperidine side chains
Bioorganic & Medicinal Chemistry Letters, 2004Co-Authors: Dongming Shen, Sander G. Mills, Kevin T. Chapman, Lorraine Malkowitz, Martin S. Springer, Sandra L. Gould, Salvatore J. Siciliano, Julie A. Demartino, Min Shu, Gloria Y KweiAbstract:Replacement of the flexible connecting chains between the piperidine moiety and an aromatic group in previous CCR5 antagonists with heterocycles, such as pyrazole and isoxazole, provided potent CCR5 antagonists with excellent anti-HIV-1 activity in vitro. SAR studies revealed optimal placement of an unsubstituted nitrogen atom in the heterocycle to be meta to the bond connected to the 4-position of piperidine. Truncation of a benzyl group to a phenyl group afforded compounds with dramatically improved oral bioavailability, albeit with reduced activity.
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1 3 4 trisubstituted pyrrolidine CCR5 Receptor antagonists modifications of the arylpropylpiperidine side chains
Bioorganic & Medicinal Chemistry Letters, 2003Co-Authors: Christopher L. Lynch, Jeffrey J. Hale, Richard J. Budhu, Amy Gentry, Edward Holson, Charles G Caldwell, Ping Chen, Christopher A Willoughby, Keith G Rosauer, Sander G. MillsAbstract:The 4-(3-phenylprop-1-yl)piperidine moiety of the 1,3,4-trisubstituted pyrrolidine CCR5 antagonist 1 was modified with electron deficient aromatics as well as replacement of the benzylic methylene with sulfones, gem-difluoromethylenes and alcohols in an effort to balance the antiviral potency with reasonable pharmacokinetics.
Sandra L. Gould - One of the best experts on this subject based on the ideXlab platform.
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potent 1 3 4 trisubstituted pyrrolidine CCR5 Receptor antagonists effects of fused heterocycles on antiviral activity and pharmacokinetic properties
Bioorganic & Medicinal Chemistry Letters, 2005Co-Authors: Liping Wang, Christopher L. Lynch, Jeffrey J. Hale, Richard J. Budhu, Sander G. Mills, Malcolm Maccoss, Lorraine Malkowitz, Sandra L. Gould, Julie A. Demartino, Martin S. SpringerAbstract:A series of 1,3,4-trisubstituted pyrrolidine CCR5 Receptor antagonists containing a variety of fused heterocycles at the 4-position of the piperidine side chain has been discovered, which are orally bioavailable with potent anti-HIV activity.
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antagonists of human CCR5 Receptor containing 4 pyrazolyl piperidine side chains part 3 sar studies on the benzylpyrazole segment
Bioorganic & Medicinal Chemistry Letters, 2004Co-Authors: Min Shu, Sander G. Mills, Kevin T. Chapman, Lorraine Malkowitz, Martin S. Springer, Sandra L. Gould, Jennifer L Loebach, Kerry A Parker, Dongming Shen, Julie A. DemartinoAbstract:Extensive SAR studies in our benzylpyrazole series of CCR5 antagonists have shown that both lipophilic and hydrophilic substituents on the phenyl of the benzyl group increase antiviral potency. However, improvements in pharmacokinetic profiles were generally only observed with more lipophilic substitutions. 4-Biphenyl (51) performed the best in this regard. Highly lipophilic substituents impart undesirable ion channel activity to these CCR5 antagonists. Alkoxy substituents provide a good balance of antiviral activity, pharmacokinetic parameters, and selectivity. Compounds 42b and 42d, containing a 3,4-dimethoxy substituent, are considered the most promising improvements over parent compounds 9. They demonstrate improved antiviral activity while retaining good pharmacokinetic profile and selectivity.
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antagonists of human CCR5 Receptor containing 4 pyrazolyl piperidine side chains part 1 discovery and sar study of 4 pyrazolylpiperidine side chains
Bioorganic & Medicinal Chemistry Letters, 2004Co-Authors: Dongming Shen, Sander G. Mills, Kevin T. Chapman, Lorraine Malkowitz, Martin S. Springer, Sandra L. Gould, Salvatore J. Siciliano, Julie A. Demartino, Min Shu, Gloria Y KweiAbstract:Replacement of the flexible connecting chains between the piperidine moiety and an aromatic group in previous CCR5 antagonists with heterocycles, such as pyrazole and isoxazole, provided potent CCR5 antagonists with excellent anti-HIV-1 activity in vitro. SAR studies revealed optimal placement of an unsubstituted nitrogen atom in the heterocycle to be meta to the bond connected to the 4-position of piperidine. Truncation of a benzyl group to a phenyl group afforded compounds with dramatically improved oral bioavailability, albeit with reduced activity.
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1,3,4-Trisubstituted pyrrolidine CCR5 Receptor antagonists. Part 4: synthesis of N-1 acidic functionality affording analogues with enhanced antiviral activity against HIV.
Bioorganic & medicinal chemistry letters, 2002Co-Authors: Christopher L. Lynch, Jeffrey J. Hale, Richard J. Budhu, Amy Gentry, Sander G. Mills, Kevin T. Chapman, Malcolm Maccoss, Lorraine Malkowitz, Martin S. Springer, Sandra L. GouldAbstract:A series of α-(pyrrolidin-1-yl)acetic acids is presented as selective and potent antivirals against HIV. Several of the pyrrolidine zwitterions demonstrated reasonable in vitro properties, enhanced antiviral activities and improved pharmacokinetic profiles over pyrrolidine 1.
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discovery of human CCR5 antagonists containing hydantoins for the treatment of hiv 1 infection
Bioorganic & Medicinal Chemistry Letters, 2001Co-Authors: Liping Wang, Sander G. Mills, Malcolm Maccoss, Lorraine Malkowitz, Sandra L. Gould, Paul E Finke, Bryan Oates, Charles G Caldwell, Ping Chen, Julie A. DemartinoAbstract:A series of hydantoin derivatives has been discovered as highly potent nonpeptide antagonists for the human CCR5 Receptor. The synthesis, SAR, and biological profiles of this class of antagonists are described.
Julie A. Demartino - One of the best experts on this subject based on the ideXlab platform.
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potent 1 3 4 trisubstituted pyrrolidine CCR5 Receptor antagonists effects of fused heterocycles on antiviral activity and pharmacokinetic properties
Bioorganic & Medicinal Chemistry Letters, 2005Co-Authors: Liping Wang, Christopher L. Lynch, Jeffrey J. Hale, Richard J. Budhu, Sander G. Mills, Malcolm Maccoss, Lorraine Malkowitz, Sandra L. Gould, Julie A. Demartino, Martin S. SpringerAbstract:A series of 1,3,4-trisubstituted pyrrolidine CCR5 Receptor antagonists containing a variety of fused heterocycles at the 4-position of the piperidine side chain has been discovered, which are orally bioavailable with potent anti-HIV activity.
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antagonists of human CCR5 Receptor containing 4 pyrazolyl piperidine side chains part 3 sar studies on the benzylpyrazole segment
Bioorganic & Medicinal Chemistry Letters, 2004Co-Authors: Min Shu, Sander G. Mills, Kevin T. Chapman, Lorraine Malkowitz, Martin S. Springer, Sandra L. Gould, Jennifer L Loebach, Kerry A Parker, Dongming Shen, Julie A. DemartinoAbstract:Extensive SAR studies in our benzylpyrazole series of CCR5 antagonists have shown that both lipophilic and hydrophilic substituents on the phenyl of the benzyl group increase antiviral potency. However, improvements in pharmacokinetic profiles were generally only observed with more lipophilic substitutions. 4-Biphenyl (51) performed the best in this regard. Highly lipophilic substituents impart undesirable ion channel activity to these CCR5 antagonists. Alkoxy substituents provide a good balance of antiviral activity, pharmacokinetic parameters, and selectivity. Compounds 42b and 42d, containing a 3,4-dimethoxy substituent, are considered the most promising improvements over parent compounds 9. They demonstrate improved antiviral activity while retaining good pharmacokinetic profile and selectivity.
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antagonists of human CCR5 Receptor containing 4 pyrazolyl piperidine side chains part 1 discovery and sar study of 4 pyrazolylpiperidine side chains
Bioorganic & Medicinal Chemistry Letters, 2004Co-Authors: Dongming Shen, Sander G. Mills, Kevin T. Chapman, Lorraine Malkowitz, Martin S. Springer, Sandra L. Gould, Salvatore J. Siciliano, Julie A. Demartino, Min Shu, Gloria Y KweiAbstract:Replacement of the flexible connecting chains between the piperidine moiety and an aromatic group in previous CCR5 antagonists with heterocycles, such as pyrazole and isoxazole, provided potent CCR5 antagonists with excellent anti-HIV-1 activity in vitro. SAR studies revealed optimal placement of an unsubstituted nitrogen atom in the heterocycle to be meta to the bond connected to the 4-position of piperidine. Truncation of a benzyl group to a phenyl group afforded compounds with dramatically improved oral bioavailability, albeit with reduced activity.
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discovery of human CCR5 antagonists containing hydantoins for the treatment of hiv 1 infection
Bioorganic & Medicinal Chemistry Letters, 2001Co-Authors: Liping Wang, Sander G. Mills, Malcolm Maccoss, Lorraine Malkowitz, Sandra L. Gould, Paul E Finke, Bryan Oates, Charles G Caldwell, Ping Chen, Julie A. DemartinoAbstract:A series of hydantoin derivatives has been discovered as highly potent nonpeptide antagonists for the human CCR5 Receptor. The synthesis, SAR, and biological profiles of this class of antagonists are described.
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1 3 4 trisubstituted pyrrolidine CCR5 Receptor antagonists part 2 lead optimization affording selective orally bioavailable compounds with potent anti hiv activity
Bioorganic & Medicinal Chemistry Letters, 2001Co-Authors: Jeffrey J. Hale, Richard J. Budhu, Sander G. Mills, Malcolm Maccoss, Sandra L. Gould, Julie A. Demartino, Edward Holson, Paul E Finke, Bryan Oates, Martin S. SpringerAbstract:Abstract Investigations of the structure–activity relationships of 1,3,4-trisubstituted pyrrolidine human CCR5 Receptor antagonists afforded orally bioavailable compounds with the ability to inhibit HIV replication in vitro.
Lorraine Malkowitz - One of the best experts on this subject based on the ideXlab platform.
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potent 1 3 4 trisubstituted pyrrolidine CCR5 Receptor antagonists effects of fused heterocycles on antiviral activity and pharmacokinetic properties
Bioorganic & Medicinal Chemistry Letters, 2005Co-Authors: Liping Wang, Christopher L. Lynch, Jeffrey J. Hale, Richard J. Budhu, Sander G. Mills, Malcolm Maccoss, Lorraine Malkowitz, Sandra L. Gould, Julie A. Demartino, Martin S. SpringerAbstract:A series of 1,3,4-trisubstituted pyrrolidine CCR5 Receptor antagonists containing a variety of fused heterocycles at the 4-position of the piperidine side chain has been discovered, which are orally bioavailable with potent anti-HIV activity.
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antagonists of human CCR5 Receptor containing 4 pyrazolyl piperidine side chains part 3 sar studies on the benzylpyrazole segment
Bioorganic & Medicinal Chemistry Letters, 2004Co-Authors: Min Shu, Sander G. Mills, Kevin T. Chapman, Lorraine Malkowitz, Martin S. Springer, Sandra L. Gould, Jennifer L Loebach, Kerry A Parker, Dongming Shen, Julie A. DemartinoAbstract:Extensive SAR studies in our benzylpyrazole series of CCR5 antagonists have shown that both lipophilic and hydrophilic substituents on the phenyl of the benzyl group increase antiviral potency. However, improvements in pharmacokinetic profiles were generally only observed with more lipophilic substitutions. 4-Biphenyl (51) performed the best in this regard. Highly lipophilic substituents impart undesirable ion channel activity to these CCR5 antagonists. Alkoxy substituents provide a good balance of antiviral activity, pharmacokinetic parameters, and selectivity. Compounds 42b and 42d, containing a 3,4-dimethoxy substituent, are considered the most promising improvements over parent compounds 9. They demonstrate improved antiviral activity while retaining good pharmacokinetic profile and selectivity.
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antagonists of human CCR5 Receptor containing 4 pyrazolyl piperidine side chains part 2 discovery of potent selective and orally bioavailable compounds
Bioorganic & Medicinal Chemistry Letters, 2004Co-Authors: Dongming Shen, Christopher L. Lynch, Jeffrey J. Hale, Sander G. Mills, Kevin T. Chapman, Lorraine Malkowitz, Christopher A Willoughby, Min Shu, Shrenik K Shah, Martin S. SpringerAbstract:Modifications of the alkyl acetic acid portion and the phenyl on pyrrolidine in our lead pyrazole compound 1 afforded the isopropyl compound 9. This compound is a potent CCR5 antagonist showing good in vitro antiviral activity against HIV-1, an excellent selectivity profile, and good oral bioavailability in three animal species. During this investigation, a new method for the preparation of α-(pyrrolidin-1-yl)-α,α-dialkyl acetic acid from a pyrrolidine and α-bromo-α,α-dialkyl acetic acid using silver triflate was discovered. This allowed us to prepare compounds such as 24 and 25 for the first time. A novel Pd-mediated N-dealkylation of α-(pyrrolidin-1-yl)acetic acid was also uncovered.
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antagonists of human CCR5 Receptor containing 4 pyrazolyl piperidine side chains part 1 discovery and sar study of 4 pyrazolylpiperidine side chains
Bioorganic & Medicinal Chemistry Letters, 2004Co-Authors: Dongming Shen, Sander G. Mills, Kevin T. Chapman, Lorraine Malkowitz, Martin S. Springer, Sandra L. Gould, Salvatore J. Siciliano, Julie A. Demartino, Min Shu, Gloria Y KweiAbstract:Replacement of the flexible connecting chains between the piperidine moiety and an aromatic group in previous CCR5 antagonists with heterocycles, such as pyrazole and isoxazole, provided potent CCR5 antagonists with excellent anti-HIV-1 activity in vitro. SAR studies revealed optimal placement of an unsubstituted nitrogen atom in the heterocycle to be meta to the bond connected to the 4-position of piperidine. Truncation of a benzyl group to a phenyl group afforded compounds with dramatically improved oral bioavailability, albeit with reduced activity.
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1,3,4-Trisubstituted pyrrolidine CCR5 Receptor antagonists. Part 4: synthesis of N-1 acidic functionality affording analogues with enhanced antiviral activity against HIV.
Bioorganic & medicinal chemistry letters, 2002Co-Authors: Christopher L. Lynch, Jeffrey J. Hale, Richard J. Budhu, Amy Gentry, Sander G. Mills, Kevin T. Chapman, Malcolm Maccoss, Lorraine Malkowitz, Martin S. Springer, Sandra L. GouldAbstract:A series of α-(pyrrolidin-1-yl)acetic acids is presented as selective and potent antivirals against HIV. Several of the pyrrolidine zwitterions demonstrated reasonable in vitro properties, enhanced antiviral activities and improved pharmacokinetic profiles over pyrrolidine 1.