Tarrant County College

Adjunct Lecturer

General Chemistry CHEM1406, CHEM1411, CHEM1412 and the associated labs.

University of Texas at Arlington

Adjunct Lecturer

CHEM2321 and CHEM2322, Organic Chemistry I and II.

Alcon Laboratories, Inc.

Director of Medicinal Chemistry

▪ Designed clinical candidate for novel Glaucoma target and managed group for identification of back-up compounds.
▪ Established program that demonstrated proof of concept for novel anti-infective target.
▪ Provided support for Glaucoma and Anti-infective therapeutic areas.
▪ Joined Novartis Institute for Biomedical Research in 2011 with Novartis Acquisition of Alcon.

Texas A&M International University

Assistant Professor

Assistant Professor of Chemistry with research interests in anti-bacterial resistance mechanisms and the design of antibacterial drugs that over come resistance mechanisms. Research into the design of small enzyme inhibitors to elucidate the role of the enzyme in diseases such as Celiac's disease, Huntington's disease, glaucoma and cancer.

Blinn College

Lecturer

Keith worked at Blinn College as a Lecturer

Volunteer Income Tax Assistance

Prepared basic tax returns for clients that met an income requirement as part of a free IRS tax service.

Structure-based design and optimization of potent inhibitors of the adenoviral protease

Bioorg Med Chem Lett.

This article describes the discovery and optimization of a series of adenain protease inhibitors. Adeno-viral infections are not currently treatable with direct pharmaceutical intervention. These compounds are a viable approach to developing new therapies for this class of viruses.

Structure-based design and optimization of potent inhibitors of the adenoviral protease

Bioorg Med Chem Lett.

This article describes the discovery and optimization of a series of adenain protease inhibitors. Adeno-viral infections are not currently treatable with direct pharmaceutical intervention. These compounds are a viable approach to developing new therapies for this class of viruses.

Impact of Substituent Modifications on the Atropselectivity Characteristics of an Anionic Oxy-Cope Ring Expansion

J. Am. Chem. Soc. 1991, 113, 1335-1344

The phenomenon of atropisomerism is critically examined in the tricyclic E,syn,up enolates derived from anionic oxy-Cope rearrangement of 1 -vinyl-2-cyclohexenyl-7,7-dimethyl-exo-norbornan-2-olass ,w ell as the ketones derived from their protonation and methylation. In all cases studied, the [3,3] sigmatropic shift proceeds with 100% stereoselectivity via the endo-chair transition-state option. The E and syn stereochemistry is established during chirality transfer at this stage. The “oxygen-up” conformation stems directly from the structural features inherent in the starting alcohols. In the unsubstituted example and with certain substitution patterns in the original cyclohexene ring, the E,syn,up enolates are seen to be thermodynamically unstable relative to their E,syn,down atropisomers, such that products result exclusively by electrophilic capture of the latter. By suitable substitution, the barrier to this preequilibrium can be sufficiently heightened so that products resulting from the E,syn,up species can be obtained. Kinetic studies involving several ketone congeners were carried out to show that the predescribed effects persist in neutral analogues as well. Epoxidation of the double bond in one example was shown to continue the trend. The global findings provide unusual insight into those factors that are most responsible for control of atropisomerism in a medium-ring setting.

Structure-based design and optimization of potent inhibitors of the adenoviral protease

Bioorg Med Chem Lett.

This article describes the discovery and optimization of a series of adenain protease inhibitors. Adeno-viral infections are not currently treatable with direct pharmaceutical intervention. These compounds are a viable approach to developing new therapies for this class of viruses.

Impact of Substituent Modifications on the Atropselectivity Characteristics of an Anionic Oxy-Cope Ring Expansion

J. Am. Chem. Soc. 1991, 113, 1335-1344

The phenomenon of atropisomerism is critically examined in the tricyclic E,syn,up enolates derived from anionic oxy-Cope rearrangement of 1 -vinyl-2-cyclohexenyl-7,7-dimethyl-exo-norbornan-2-olass ,w ell as the ketones derived from their protonation and methylation. In all cases studied, the [3,3] sigmatropic shift proceeds with 100% stereoselectivity via the endo-chair transition-state option. The E and syn stereochemistry is established during chirality transfer at this stage. The “oxygen-up” conformation stems directly from the structural features inherent in the starting alcohols. In the unsubstituted example and with certain substitution patterns in the original cyclohexene ring, the E,syn,up enolates are seen to be thermodynamically unstable relative to their E,syn,down atropisomers, such that products result exclusively by electrophilic capture of the latter. By suitable substitution, the barrier to this preequilibrium can be sufficiently heightened so that products resulting from the E,syn,up species can be obtained. Kinetic studies involving several ketone congeners were carried out to show that the predescribed effects persist in neutral analogues as well. Epoxidation of the double bond in one example was shown to continue the trend. The global findings provide unusual insight into those factors that are most responsible for control of atropisomerism in a medium-ring setting.

Rifamycin derivatives active against pathogenic rapidly-growing mycobacteria

Bioorganic and Medicinal Chemistry Letters

This article describes our recent work on Mycobacterium abscessus and other rapidly growing mycobacteria with a series of Rifamycin analogs. These compounds completely restore rifampin like activity in an organism that is naturally resistant to rifampicin.

Structure-based design and optimization of potent inhibitors of the adenoviral protease

Bioorg Med Chem Lett.

This article describes the discovery and optimization of a series of adenain protease inhibitors. Adeno-viral infections are not currently treatable with direct pharmaceutical intervention. These compounds are a viable approach to developing new therapies for this class of viruses.

Impact of Substituent Modifications on the Atropselectivity Characteristics of an Anionic Oxy-Cope Ring Expansion

J. Am. Chem. Soc. 1991, 113, 1335-1344

The phenomenon of atropisomerism is critically examined in the tricyclic E,syn,up enolates derived from anionic oxy-Cope rearrangement of 1 -vinyl-2-cyclohexenyl-7,7-dimethyl-exo-norbornan-2-olass ,w ell as the ketones derived from their protonation and methylation. In all cases studied, the [3,3] sigmatropic shift proceeds with 100% stereoselectivity via the endo-chair transition-state option. The E and syn stereochemistry is established during chirality transfer at this stage. The “oxygen-up” conformation stems directly from the structural features inherent in the starting alcohols. In the unsubstituted example and with certain substitution patterns in the original cyclohexene ring, the E,syn,up enolates are seen to be thermodynamically unstable relative to their E,syn,down atropisomers, such that products result exclusively by electrophilic capture of the latter. By suitable substitution, the barrier to this preequilibrium can be sufficiently heightened so that products resulting from the E,syn,up species can be obtained. Kinetic studies involving several ketone congeners were carried out to show that the predescribed effects persist in neutral analogues as well. Epoxidation of the double bond in one example was shown to continue the trend. The global findings provide unusual insight into those factors that are most responsible for control of atropisomerism in a medium-ring setting.

Rifamycin derivatives active against pathogenic rapidly-growing mycobacteria

Bioorganic and Medicinal Chemistry Letters

This article describes our recent work on Mycobacterium abscessus and other rapidly growing mycobacteria with a series of Rifamycin analogs. These compounds completely restore rifampin like activity in an organism that is naturally resistant to rifampicin.

Discovery and Structure-Based Optimization of Adenain Inhibitors

ACS Medicinal Chemistry Letters

The cysteine protease adenain is the essential protease of adenovirus and, as such, represents a promising target for the treatment of ocular and other adenoviral infections. Through a concise two-pronged hit discovery approach we identified tetrapeptide nitrile 1 and pyrimidine nitrile 2 as complementary starting points for adenain inhibition. These hits enabled the first high-resolution X-ray cocrystal structures of adenain with inhibitors bound and revealed the binding mode of 1 and 2 screening hits were optimized by a structure-guided medicinal chemistry strategy into low nanomolar drug-like inhibitors of adenain.

Structure-based design and optimization of potent inhibitors of the adenoviral protease

Bioorg Med Chem Lett.

This article describes the discovery and optimization of a series of adenain protease inhibitors. Adeno-viral infections are not currently treatable with direct pharmaceutical intervention. These compounds are a viable approach to developing new therapies for this class of viruses.

Impact of Substituent Modifications on the Atropselectivity Characteristics of an Anionic Oxy-Cope Ring Expansion

J. Am. Chem. Soc. 1991, 113, 1335-1344

The phenomenon of atropisomerism is critically examined in the tricyclic E,syn,up enolates derived from anionic oxy-Cope rearrangement of 1 -vinyl-2-cyclohexenyl-7,7-dimethyl-exo-norbornan-2-olass ,w ell as the ketones derived from their protonation and methylation. In all cases studied, the [3,3] sigmatropic shift proceeds with 100% stereoselectivity via the endo-chair transition-state option. The E and syn stereochemistry is established during chirality transfer at this stage. The “oxygen-up” conformation stems directly from the structural features inherent in the starting alcohols. In the unsubstituted example and with certain substitution patterns in the original cyclohexene ring, the E,syn,up enolates are seen to be thermodynamically unstable relative to their E,syn,down atropisomers, such that products result exclusively by electrophilic capture of the latter. By suitable substitution, the barrier to this preequilibrium can be sufficiently heightened so that products resulting from the E,syn,up species can be obtained. Kinetic studies involving several ketone congeners were carried out to show that the predescribed effects persist in neutral analogues as well. Epoxidation of the double bond in one example was shown to continue the trend. The global findings provide unusual insight into those factors that are most responsible for control of atropisomerism in a medium-ring setting.

Rifamycin derivatives active against pathogenic rapidly-growing mycobacteria

Bioorganic and Medicinal Chemistry Letters

This article describes our recent work on Mycobacterium abscessus and other rapidly growing mycobacteria with a series of Rifamycin analogs. These compounds completely restore rifampin like activity in an organism that is naturally resistant to rifampicin.

Discovery and Structure-Based Optimization of Adenain Inhibitors

ACS Medicinal Chemistry Letters

The cysteine protease adenain is the essential protease of adenovirus and, as such, represents a promising target for the treatment of ocular and other adenoviral infections. Through a concise two-pronged hit discovery approach we identified tetrapeptide nitrile 1 and pyrimidine nitrile 2 as complementary starting points for adenain inhibition. These hits enabled the first high-resolution X-ray cocrystal structures of adenain with inhibitors bound and revealed the binding mode of 1 and 2 screening hits were optimized by a structure-guided medicinal chemistry strategy into low nanomolar drug-like inhibitors of adenain.

Discovery and Early Clinical Evaluation of BMS-605339, a Potent and Orally Efficacious Tripeptidic Acylsulfonamide NS3 Protease Inhibitor for the Treatment of Hepatitis C Virus Infection

Journal of Medicial Chemistry

Discovery and Early Clinical Evaluation of BMS-605339, a Potent and Orally Efficacious Tripeptidic Acylsulfonamide NS3 Protease Inhibitor for the Treatment of Hepatitis C Virus Infection.

Structure-based design and optimization of potent inhibitors of the adenoviral protease

Bioorg Med Chem Lett.

This article describes the discovery and optimization of a series of adenain protease inhibitors. Adeno-viral infections are not currently treatable with direct pharmaceutical intervention. These compounds are a viable approach to developing new therapies for this class of viruses.

Impact of Substituent Modifications on the Atropselectivity Characteristics of an Anionic Oxy-Cope Ring Expansion

J. Am. Chem. Soc. 1991, 113, 1335-1344

The phenomenon of atropisomerism is critically examined in the tricyclic E,syn,up enolates derived from anionic oxy-Cope rearrangement of 1 -vinyl-2-cyclohexenyl-7,7-dimethyl-exo-norbornan-2-olass ,w ell as the ketones derived from their protonation and methylation. In all cases studied, the [3,3] sigmatropic shift proceeds with 100% stereoselectivity via the endo-chair transition-state option. The E and syn stereochemistry is established during chirality transfer at this stage. The “oxygen-up” conformation stems directly from the structural features inherent in the starting alcohols. In the unsubstituted example and with certain substitution patterns in the original cyclohexene ring, the E,syn,up enolates are seen to be thermodynamically unstable relative to their E,syn,down atropisomers, such that products result exclusively by electrophilic capture of the latter. By suitable substitution, the barrier to this preequilibrium can be sufficiently heightened so that products resulting from the E,syn,up species can be obtained. Kinetic studies involving several ketone congeners were carried out to show that the predescribed effects persist in neutral analogues as well. Epoxidation of the double bond in one example was shown to continue the trend. The global findings provide unusual insight into those factors that are most responsible for control of atropisomerism in a medium-ring setting.

Rifamycin derivatives active against pathogenic rapidly-growing mycobacteria

Bioorganic and Medicinal Chemistry Letters

This article describes our recent work on Mycobacterium abscessus and other rapidly growing mycobacteria with a series of Rifamycin analogs. These compounds completely restore rifampin like activity in an organism that is naturally resistant to rifampicin.

Discovery and Structure-Based Optimization of Adenain Inhibitors

ACS Medicinal Chemistry Letters

The cysteine protease adenain is the essential protease of adenovirus and, as such, represents a promising target for the treatment of ocular and other adenoviral infections. Through a concise two-pronged hit discovery approach we identified tetrapeptide nitrile 1 and pyrimidine nitrile 2 as complementary starting points for adenain inhibition. These hits enabled the first high-resolution X-ray cocrystal structures of adenain with inhibitors bound and revealed the binding mode of 1 and 2 screening hits were optimized by a structure-guided medicinal chemistry strategy into low nanomolar drug-like inhibitors of adenain.

Discovery and Early Clinical Evaluation of BMS-605339, a Potent and Orally Efficacious Tripeptidic Acylsulfonamide NS3 Protease Inhibitor for the Treatment of Hepatitis C Virus Infection

Journal of Medicial Chemistry

Discovery and Early Clinical Evaluation of BMS-605339, a Potent and Orally Efficacious Tripeptidic Acylsulfonamide NS3 Protease Inhibitor for the Treatment of Hepatitis C Virus Infection.

Structure-based design and optimization of potent inhibitors of adenoviral protease inhibitor

Bioorganic & Medicinal Chemistry Letters/ Elsevier

Adenoviral infections are associated with a wide range of acute diseases, among which ocular viral conjunctivitis (EKC) and disseminated disease in immunocompromised patients. To date, no approved specific anti-adenoviral drug is available, but there is a growing need for an effective treatment of such infections. The adenoviral protease, adenain, plays a crucial role for the viral lifecycle and thus represents an attractive therapeutic target. Structure-guided design with the objective to depeptidize tetrapeptide nitrile 1 led to the novel chemotype 2. Optimization of scaffold 2 resulted in picomolar adenain inhibitors 3a and 3b. In addition, a complementary series of irreversible vinyl sulfone containing inhibitors were rationally designed, prepared and evaluated against adenoviral protease. High resolution X-ray co-crystal structures of representatives of each series proves the successful design of these inhibitors and provides an excellent basis for future medicinal chemistry optimization of these compounds.

Structure-based design and optimization of potent inhibitors of the adenoviral protease

Bioorg Med Chem Lett.

This article describes the discovery and optimization of a series of adenain protease inhibitors. Adeno-viral infections are not currently treatable with direct pharmaceutical intervention. These compounds are a viable approach to developing new therapies for this class of viruses.

Impact of Substituent Modifications on the Atropselectivity Characteristics of an Anionic Oxy-Cope Ring Expansion

J. Am. Chem. Soc. 1991, 113, 1335-1344

The phenomenon of atropisomerism is critically examined in the tricyclic E,syn,up enolates derived from anionic oxy-Cope rearrangement of 1 -vinyl-2-cyclohexenyl-7,7-dimethyl-exo-norbornan-2-olass ,w ell as the ketones derived from their protonation and methylation. In all cases studied, the [3,3] sigmatropic shift proceeds with 100% stereoselectivity via the endo-chair transition-state option. The E and syn stereochemistry is established during chirality transfer at this stage. The “oxygen-up” conformation stems directly from the structural features inherent in the starting alcohols. In the unsubstituted example and with certain substitution patterns in the original cyclohexene ring, the E,syn,up enolates are seen to be thermodynamically unstable relative to their E,syn,down atropisomers, such that products result exclusively by electrophilic capture of the latter. By suitable substitution, the barrier to this preequilibrium can be sufficiently heightened so that products resulting from the E,syn,up species can be obtained. Kinetic studies involving several ketone congeners were carried out to show that the predescribed effects persist in neutral analogues as well. Epoxidation of the double bond in one example was shown to continue the trend. The global findings provide unusual insight into those factors that are most responsible for control of atropisomerism in a medium-ring setting.

Rifamycin derivatives active against pathogenic rapidly-growing mycobacteria

Bioorganic and Medicinal Chemistry Letters

This article describes our recent work on Mycobacterium abscessus and other rapidly growing mycobacteria with a series of Rifamycin analogs. These compounds completely restore rifampin like activity in an organism that is naturally resistant to rifampicin.

Discovery and Structure-Based Optimization of Adenain Inhibitors

ACS Medicinal Chemistry Letters

The cysteine protease adenain is the essential protease of adenovirus and, as such, represents a promising target for the treatment of ocular and other adenoviral infections. Through a concise two-pronged hit discovery approach we identified tetrapeptide nitrile 1 and pyrimidine nitrile 2 as complementary starting points for adenain inhibition. These hits enabled the first high-resolution X-ray cocrystal structures of adenain with inhibitors bound and revealed the binding mode of 1 and 2 screening hits were optimized by a structure-guided medicinal chemistry strategy into low nanomolar drug-like inhibitors of adenain.

Discovery and Early Clinical Evaluation of BMS-605339, a Potent and Orally Efficacious Tripeptidic Acylsulfonamide NS3 Protease Inhibitor for the Treatment of Hepatitis C Virus Infection

Journal of Medicial Chemistry

Discovery and Early Clinical Evaluation of BMS-605339, a Potent and Orally Efficacious Tripeptidic Acylsulfonamide NS3 Protease Inhibitor for the Treatment of Hepatitis C Virus Infection.

Structure-based design and optimization of potent inhibitors of adenoviral protease inhibitor

Bioorganic & Medicinal Chemistry Letters/ Elsevier

Adenoviral infections are associated with a wide range of acute diseases, among which ocular viral conjunctivitis (EKC) and disseminated disease in immunocompromised patients. To date, no approved specific anti-adenoviral drug is available, but there is a growing need for an effective treatment of such infections. The adenoviral protease, adenain, plays a crucial role for the viral lifecycle and thus represents an attractive therapeutic target. Structure-guided design with the objective to depeptidize tetrapeptide nitrile 1 led to the novel chemotype 2. Optimization of scaffold 2 resulted in picomolar adenain inhibitors 3a and 3b. In addition, a complementary series of irreversible vinyl sulfone containing inhibitors were rationally designed, prepared and evaluated against adenoviral protease. High resolution X-ray co-crystal structures of representatives of each series proves the successful design of these inhibitors and provides an excellent basis for future medicinal chemistry optimization of these compounds.

New C25 carbamate rifamycin derivatives are resistant to inactivation by ADP-ribosyl transferases

Bioorganic Chemistry and Medicinal Chemisty Letters/Elsevier

A novel series of 3-morpholino rifamycins in which the C25 acetate group was replaced by a carbamate group were prepared and found to exhibit significantly improved antimicrobial activity than rifampin against Mycobacterium smegmatis. Further characterization of such compounds suggests that relatively large groups attached to the rifamycin core via a C25 carbamate linkage prevent inactivation via ribosylation of the C23 alcohol as catalyzed by the endogenous rifampin ADP-ribosyl transferase of M. smegmatis. SAR studies of the C25 carbamate rifamycin series against M. smegmatis and other bacteria are reported. Keywords: rifamycin; carbamate; adp-ribosyl; adp-ribosyl transferase; smegmaty; rifamycin derivative; transferase; rifampin; inactivation; derivative; resistant; sar; group; carbamate group; ribosylation;

Structure-based design and optimization of potent inhibitors of the adenoviral protease

Bioorg Med Chem Lett.

This article describes the discovery and optimization of a series of adenain protease inhibitors. Adeno-viral infections are not currently treatable with direct pharmaceutical intervention. These compounds are a viable approach to developing new therapies for this class of viruses.

Impact of Substituent Modifications on the Atropselectivity Characteristics of an Anionic Oxy-Cope Ring Expansion

J. Am. Chem. Soc. 1991, 113, 1335-1344

The phenomenon of atropisomerism is critically examined in the tricyclic E,syn,up enolates derived from anionic oxy-Cope rearrangement of 1 -vinyl-2-cyclohexenyl-7,7-dimethyl-exo-norbornan-2-olass ,w ell as the ketones derived from their protonation and methylation. In all cases studied, the [3,3] sigmatropic shift proceeds with 100% stereoselectivity via the endo-chair transition-state option. The E and syn stereochemistry is established during chirality transfer at this stage. The “oxygen-up” conformation stems directly from the structural features inherent in the starting alcohols. In the unsubstituted example and with certain substitution patterns in the original cyclohexene ring, the E,syn,up enolates are seen to be thermodynamically unstable relative to their E,syn,down atropisomers, such that products result exclusively by electrophilic capture of the latter. By suitable substitution, the barrier to this preequilibrium can be sufficiently heightened so that products resulting from the E,syn,up species can be obtained. Kinetic studies involving several ketone congeners were carried out to show that the predescribed effects persist in neutral analogues as well. Epoxidation of the double bond in one example was shown to continue the trend. The global findings provide unusual insight into those factors that are most responsible for control of atropisomerism in a medium-ring setting.

Rifamycin derivatives active against pathogenic rapidly-growing mycobacteria

Bioorganic and Medicinal Chemistry Letters

This article describes our recent work on Mycobacterium abscessus and other rapidly growing mycobacteria with a series of Rifamycin analogs. These compounds completely restore rifampin like activity in an organism that is naturally resistant to rifampicin.

Discovery and Structure-Based Optimization of Adenain Inhibitors

ACS Medicinal Chemistry Letters

The cysteine protease adenain is the essential protease of adenovirus and, as such, represents a promising target for the treatment of ocular and other adenoviral infections. Through a concise two-pronged hit discovery approach we identified tetrapeptide nitrile 1 and pyrimidine nitrile 2 as complementary starting points for adenain inhibition. These hits enabled the first high-resolution X-ray cocrystal structures of adenain with inhibitors bound and revealed the binding mode of 1 and 2 screening hits were optimized by a structure-guided medicinal chemistry strategy into low nanomolar drug-like inhibitors of adenain.

Discovery and Early Clinical Evaluation of BMS-605339, a Potent and Orally Efficacious Tripeptidic Acylsulfonamide NS3 Protease Inhibitor for the Treatment of Hepatitis C Virus Infection

Journal of Medicial Chemistry

Discovery and Early Clinical Evaluation of BMS-605339, a Potent and Orally Efficacious Tripeptidic Acylsulfonamide NS3 Protease Inhibitor for the Treatment of Hepatitis C Virus Infection.

Structure-based design and optimization of potent inhibitors of adenoviral protease inhibitor

Bioorganic & Medicinal Chemistry Letters/ Elsevier

Adenoviral infections are associated with a wide range of acute diseases, among which ocular viral conjunctivitis (EKC) and disseminated disease in immunocompromised patients. To date, no approved specific anti-adenoviral drug is available, but there is a growing need for an effective treatment of such infections. The adenoviral protease, adenain, plays a crucial role for the viral lifecycle and thus represents an attractive therapeutic target. Structure-guided design with the objective to depeptidize tetrapeptide nitrile 1 led to the novel chemotype 2. Optimization of scaffold 2 resulted in picomolar adenain inhibitors 3a and 3b. In addition, a complementary series of irreversible vinyl sulfone containing inhibitors were rationally designed, prepared and evaluated against adenoviral protease. High resolution X-ray co-crystal structures of representatives of each series proves the successful design of these inhibitors and provides an excellent basis for future medicinal chemistry optimization of these compounds.

New C25 carbamate rifamycin derivatives are resistant to inactivation by ADP-ribosyl transferases

Bioorganic Chemistry and Medicinal Chemisty Letters/Elsevier

A novel series of 3-morpholino rifamycins in which the C25 acetate group was replaced by a carbamate group were prepared and found to exhibit significantly improved antimicrobial activity than rifampin against Mycobacterium smegmatis. Further characterization of such compounds suggests that relatively large groups attached to the rifamycin core via a C25 carbamate linkage prevent inactivation via ribosylation of the C23 alcohol as catalyzed by the endogenous rifampin ADP-ribosyl transferase of M. smegmatis. SAR studies of the C25 carbamate rifamycin series against M. smegmatis and other bacteria are reported. Keywords: rifamycin; carbamate; adp-ribosyl; adp-ribosyl transferase; smegmaty; rifamycin derivative; transferase; rifampin; inactivation; derivative; resistant; sar; group; carbamate group; ribosylation;

In vivo optimization of 2,3-diaminopyrazine Rho Kinase inhibitors for the treatment of glaucoma

Bioorganic & Medicinal Chemistry Letters

Structure-based design and optimization of potent inhibitors of the adenoviral protease

Bioorg Med Chem Lett.

This article describes the discovery and optimization of a series of adenain protease inhibitors. Adeno-viral infections are not currently treatable with direct pharmaceutical intervention. These compounds are a viable approach to developing new therapies for this class of viruses.

Impact of Substituent Modifications on the Atropselectivity Characteristics of an Anionic Oxy-Cope Ring Expansion

J. Am. Chem. Soc. 1991, 113, 1335-1344

The phenomenon of atropisomerism is critically examined in the tricyclic E,syn,up enolates derived from anionic oxy-Cope rearrangement of 1 -vinyl-2-cyclohexenyl-7,7-dimethyl-exo-norbornan-2-olass ,w ell as the ketones derived from their protonation and methylation. In all cases studied, the [3,3] sigmatropic shift proceeds with 100% stereoselectivity via the endo-chair transition-state option. The E and syn stereochemistry is established during chirality transfer at this stage. The “oxygen-up” conformation stems directly from the structural features inherent in the starting alcohols. In the unsubstituted example and with certain substitution patterns in the original cyclohexene ring, the E,syn,up enolates are seen to be thermodynamically unstable relative to their E,syn,down atropisomers, such that products result exclusively by electrophilic capture of the latter. By suitable substitution, the barrier to this preequilibrium can be sufficiently heightened so that products resulting from the E,syn,up species can be obtained. Kinetic studies involving several ketone congeners were carried out to show that the predescribed effects persist in neutral analogues as well. Epoxidation of the double bond in one example was shown to continue the trend. The global findings provide unusual insight into those factors that are most responsible for control of atropisomerism in a medium-ring setting.

Rifamycin derivatives active against pathogenic rapidly-growing mycobacteria

Bioorganic and Medicinal Chemistry Letters

This article describes our recent work on Mycobacterium abscessus and other rapidly growing mycobacteria with a series of Rifamycin analogs. These compounds completely restore rifampin like activity in an organism that is naturally resistant to rifampicin.

Discovery and Structure-Based Optimization of Adenain Inhibitors

ACS Medicinal Chemistry Letters

The cysteine protease adenain is the essential protease of adenovirus and, as such, represents a promising target for the treatment of ocular and other adenoviral infections. Through a concise two-pronged hit discovery approach we identified tetrapeptide nitrile 1 and pyrimidine nitrile 2 as complementary starting points for adenain inhibition. These hits enabled the first high-resolution X-ray cocrystal structures of adenain with inhibitors bound and revealed the binding mode of 1 and 2 screening hits were optimized by a structure-guided medicinal chemistry strategy into low nanomolar drug-like inhibitors of adenain.

Discovery and Early Clinical Evaluation of BMS-605339, a Potent and Orally Efficacious Tripeptidic Acylsulfonamide NS3 Protease Inhibitor for the Treatment of Hepatitis C Virus Infection

Journal of Medicial Chemistry

Discovery and Early Clinical Evaluation of BMS-605339, a Potent and Orally Efficacious Tripeptidic Acylsulfonamide NS3 Protease Inhibitor for the Treatment of Hepatitis C Virus Infection.

Structure-based design and optimization of potent inhibitors of adenoviral protease inhibitor

Bioorganic & Medicinal Chemistry Letters/ Elsevier

Adenoviral infections are associated with a wide range of acute diseases, among which ocular viral conjunctivitis (EKC) and disseminated disease in immunocompromised patients. To date, no approved specific anti-adenoviral drug is available, but there is a growing need for an effective treatment of such infections. The adenoviral protease, adenain, plays a crucial role for the viral lifecycle and thus represents an attractive therapeutic target. Structure-guided design with the objective to depeptidize tetrapeptide nitrile 1 led to the novel chemotype 2. Optimization of scaffold 2 resulted in picomolar adenain inhibitors 3a and 3b. In addition, a complementary series of irreversible vinyl sulfone containing inhibitors were rationally designed, prepared and evaluated against adenoviral protease. High resolution X-ray co-crystal structures of representatives of each series proves the successful design of these inhibitors and provides an excellent basis for future medicinal chemistry optimization of these compounds.

New C25 carbamate rifamycin derivatives are resistant to inactivation by ADP-ribosyl transferases

Bioorganic Chemistry and Medicinal Chemisty Letters/Elsevier

A novel series of 3-morpholino rifamycins in which the C25 acetate group was replaced by a carbamate group were prepared and found to exhibit significantly improved antimicrobial activity than rifampin against Mycobacterium smegmatis. Further characterization of such compounds suggests that relatively large groups attached to the rifamycin core via a C25 carbamate linkage prevent inactivation via ribosylation of the C23 alcohol as catalyzed by the endogenous rifampin ADP-ribosyl transferase of M. smegmatis. SAR studies of the C25 carbamate rifamycin series against M. smegmatis and other bacteria are reported. Keywords: rifamycin; carbamate; adp-ribosyl; adp-ribosyl transferase; smegmaty; rifamycin derivative; transferase; rifampin; inactivation; derivative; resistant; sar; group; carbamate group; ribosylation;

In vivo optimization of 2,3-diaminopyrazine Rho Kinase inhibitors for the treatment of glaucoma

Bioorganic & Medicinal Chemistry Letters