ACS Pharmacology and Translational Science最新文献

This study presents a novel series of N-acylated 1,2,4-triazol-5-amines and 1H-pyrazol-5-amines, featuring a pyrazin-2-yl moiety, developed as covalent inhibitors of thrombin. These compounds demonstrated potent inhibitory activity, with derivatives 13a and 13b achieving IC₅₀ values as low as 0.7 and 0.8 nM, respectively. Mass-shift assays confirmed that these inhibitors covalently bind to the catalytic Ser195 of thrombin, leading to temporary inhibition of its activity through specific acylation. The anticoagulant efficacy of these compounds was validated in plasma coagulation assays, with selected derivatives extending coagulation times in both an activated partial thromboplastin time (aPTT) and prothrombin time (PT) test. Thrombin generation assays further demonstrated that compounds of this series effectively reduced thrombin generation without substantially prolonging clotting times, suggesting a lower risk of bleeding. Selected compounds also strongly inhibited cancer cell- and thrombin-induced platelet aggregation. These results indicate that acylated aminoazoles hold a promise as new anticoagulants.

Infectious diseases have affected 13.7 million patients, placing a heavy burden on society. Furthermore, inappropriate and unrequited utilization of antibiotics has led to antimicrobial resistance worldwide. However, well-established targeted screening of environmental isolates or compound libraries has produced limited new drugs. The current situation, in which drug development is delayed, bacterial evolution is occurring, and drug resistance is emerging, requires the development of new targets and/or new strategies to combat infections. Some novel antibacterial strategies have been proposed, among which disruption of protein balance by inhibiting transcription and translation machinery is one of the proven effective antimicrobial strategies. Molecular chaperonins could mediate the correct folding of proteins, especially under conditions such as high temperature and pressure. The GroEL/ES system has been confirmed as one of the key molecular chaperones for bacterial viability. Recent data have revealed the antibacterial activities of GroEL/ES-targeted compounds, highlighting the potential role of GroEL/ES in the development of novel antibiotics. In this brief review, we discuss the function of the GroEL/ES system and summarize the inhibitors of the GroEL/ES system. The GroEL/ES system may represent a promising drug target for the exploration of novel antibiotics.

Infectious diseases have affected 13.7 million patients, placing a heavy burden on society. Furthermore, inappropriate and unrequited utilization of antibiotics has led to antimicrobial resistance worldwide. However, well-established targeted screening of environmental isolates or compound libraries has produced limited new drugs. The current situation, in which drug development is delayed, bacterial evolution is occurring, and drug resistance is emerging, requires the development of new targets and/or new strategies to combat infections. Some novel antibacterial strategies have been proposed, among which disruption of protein balance by inhibiting transcription and translation machinery is one of the proven effective antimicrobial strategies. Molecular chaperonins could mediate the correct folding of proteins, especially under conditions such as high temperature and pressure. The GroEL/ES system has been confirmed as one of the key molecular chaperones for bacterial viability. Recent data have revealed the antibacterial activities of GroEL/ES-targeted compounds, highlighting the potential role of GroEL/ES in the development of novel antibiotics. In this brief review, we discuss the function of the GroEL/ES system and summarize the inhibitors of the GroEL/ES system. The GroEL/ES system may represent a promising drug target for the exploration of novel antibiotics.

This study presents a novel series of N-acylated 1,2,4-triazol-5-amines and 1H-pyrazol-5-amines, featuring a pyrazin-2-yl moiety, developed as covalent inhibitors of thrombin. These compounds demonstrated potent inhibitory activity, with derivatives 13a and 13b achieving IC₅₀ values as low as 0.7 and 0.8 nM, respectively. Mass-shift assays confirmed that these inhibitors covalently bind to the catalytic Ser195 of thrombin, leading to temporary inhibition of its activity through specific acylation. The anticoagulant efficacy of these compounds was validated in plasma coagulation assays, with selected derivatives extending coagulation times in both an activated partial thromboplastin time (aPTT) and prothrombin time (PT) test. Thrombin generation assays further demonstrated that compounds of this series effectively reduced thrombin generation without substantially prolonging clotting times, suggesting a lower risk of bleeding. Selected compounds also strongly inhibited cancer cell- and thrombin-induced platelet aggregation. These results indicate that acylated aminoazoles hold a promise as new anticoagulants.

Erythroferrone (ERFE) has emerged as a potential biomarker for the erythropoiesis response following recombinant human erythropoietin (rHuEPO) treatment. While the association between ERFE and hemoglobin (HGB) response to rHuEPO is well-established in nonanemic conditions, such correlation and ERFE kinetics in anemic states remain unclear. We employed two rat models of anemia, chronic kidney disease (CKD) anemia and chemotherapy-induced anemia (CIA), to determine ERFE kinetics and its correlation with HGB responses after rHuEPO administration. The key factors influencing ERFE kinetics were characterized using a PK/PD modeling approach and supported by experimentation. Following rHuEPO injection, ERFE induction was diminished in anemic rats compared with that of healthy rats, primarily attributed to the reduced precursor cell mass and impaired rHuEPO responsiveness. The early increase in ERFE at 4 h post administration allows for the prompt prediction of HGB response and rHuEPO hyporesponsiveness in anemic rats. Consequently, the ERFE-based dose adjustment resulted in a rHuEPO-sparing effect in CKD rats. This strategy is expected to be translatable to anemic patients, potentially reducing rHuEPO doses and mitigating HGB overshooting.

Erythroferrone (ERFE) has emerged as a potential biomarker for the erythropoiesis response following recombinant human erythropoietin (rHuEPO) treatment. While the association between ERFE and hemoglobin (HGB) response to rHuEPO is well-established in nonanemic conditions, such correlation and ERFE kinetics in anemic states remain unclear. We employed two rat models of anemia, chronic kidney disease (CKD) anemia and chemotherapy-induced anemia (CIA), to determine ERFE kinetics and its correlation with HGB responses after rHuEPO administration. The key factors influencing ERFE kinetics were characterized using a PK/PD modeling approach and supported by experimentation. Following rHuEPO injection, ERFE induction was diminished in anemic rats compared with that of healthy rats, primarily attributed to the reduced precursor cell mass and impaired rHuEPO responsiveness. The early increase in ERFE at 4 h post administration allows for the prompt prediction of HGB response and rHuEPO hyporesponsiveness in anemic rats. Consequently, the ERFE-based dose adjustment resulted in a rHuEPO-sparing effect in CKD rats. This strategy is expected to be translatable to anemic patients, potentially reducing rHuEPO doses and mitigating HGB overshooting.

Despite the enthusiasm for targeted cancer therapies in preclinical studies and the success of a select few drugs, many promising drug candidates fail in clinical trials. The gap between preclinical promise and clinical outcomes underscores the need to investigate factors influencing the success or failure of targeted therapies. Dasatinib, an inhibitor of Abl and Src protein tyrosine kinases, is highly effective toward chronic myeloid leukemia (CML) by targeting BCR-Abl, but it is ineffective against solid tumors when targeting Src kinases. A review reveals cytotoxic inhibition is a key attribute predictive of dasatinib’s clinical efficacy toward CML, and cytostatic inhibition by targeting Src kinases is the underlying reason for the preclinical promise and clinical inefficacy toward solid tumors. The analysis reveals that preclinical cytotoxic inhibition is highly predictive of clinical efficacy and shows that cancer regression can only be achieved when the drug–target is an essential oncogenic driver in a monodriver cancer. The analysis highlights dasatinib’s potential in achieving stable disease in solid tumors, supporting its use in combination therapies.

Despite the enthusiasm for targeted cancer therapies in preclinical studies and the success of a select few drugs, many promising drug candidates fail in clinical trials. The gap between preclinical promise and clinical outcomes underscores the need to investigate factors influencing the success or failure of targeted therapies. Dasatinib, an inhibitor of Abl and Src protein tyrosine kinases, is highly effective toward chronic myeloid leukemia (CML) by targeting BCR-Abl, but it is ineffective against solid tumors when targeting Src kinases. A review reveals cytotoxic inhibition is a key attribute predictive of dasatinib's clinical efficacy toward CML, and cytostatic inhibition by targeting Src kinases is the underlying reason for the preclinical promise and clinical inefficacy toward solid tumors. The analysis reveals that preclinical cytotoxic inhibition is highly predictive of clinical efficacy and shows that cancer regression can only be achieved when the drug-target is an essential oncogenic driver in a monodriver cancer. The analysis highlights dasatinib's potential in achieving stable disease in solid tumors, supporting its use in combination therapies.

The development of highly potent and selective μ opioid receptor (MOR) modulators with favorable drug-like properties has always been a focus in the opioid domain. Our previous efforts led to the discovery of a lead compound designated as NAT, a potent centrally acting MOR modulator. However, the fact that NAT precipitated considerable withdrawal effects at higher doses largely impaired its further development. In the light of the concept of activity cliff and CNS multiparameter optimization algorithm, a nitrogen atom was incorporated into the thiophene ring of NAT, aiming to preserve desirable pharmacological activities and CNS permeability while alleviating withdrawal symptoms. Among all 16 new analogs, compound 6 (NTZ) exhibited improved opioid receptor selectivity, enhanced in vivo antagonistic effect, and overall fewer withdrawal symptoms compared to NAT. Further assessment of several key drug-like properties suggested a favorable ADMET profile of NTZ. Taken together, NTZ shows promise as a potential lead to treat opioid use disorder.

The development of highly potent and selective μ opioid receptor (MOR) modulators with favorable drug-like properties has always been a focus in the opioid domain. Our previous efforts led to the discovery of a lead compound designated as NAT, a potent centrally acting MOR modulator. However, the fact that NAT precipitated considerable withdrawal effects at higher doses largely impaired its further development. In the light of the concept of activity cliff and CNS multiparameter optimization algorithm, a nitrogen atom was incorporated into the thiophene ring of NAT, aiming to preserve desirable pharmacological activities and CNS permeability while alleviating withdrawal symptoms. Among all 16 new analogs, compound 6 (NTZ) exhibited improved opioid receptor selectivity, enhanced in vivo antagonistic effect, and overall fewer withdrawal symptoms compared to NAT. Further assessment of several key drug-like properties suggested a favorable ADMET profile of NTZ. Taken together, NTZ shows promise as a potential lead to treat opioid use disorder.