Structure-Based Design of Novel G‑Protein-Coupled Receptor TAAR1 Agonists as Potential Antipsychotic Drug Candidates

The existing available antipsychotics have failed to manage the cognitive impairment of schizophrenia and induced a number of seriously undesirable effects. Trace amine-associated receptor 1 (TAAR1) has emerged as an ideal target for the design of antischizophrenia drugs, with the ability to mediate multiple psychological functions by sensing endogenous amine-containing metabolites without the side effects of catalepsy. In this work, a series of novel TAAR1 agonists were designed based on the structural analysis of the TAAR1 activation pocket. Among them, 6e displayed a potent TAAR1-Gs/Gq dual-pathway activation property, being different from that of the clinical drug candidate SEP-363856 with only TAAR1-Gs pathway activation. In rodent models, 6e significantly alleviated MK-801-induced schizophrenia-like cognitive phenotypes without inducing catalepsy. Furthermore, 6e·HCl exhibited favorable pharmacokinetic (T1/2 = 2.31 h, F = 39%) and safety properties. All these demonstrated that 6e·HCl may be used as a novel drug candidate for schizophrenia treatment

Structure-Based Design of Novel G‑Protein-Coupled Receptor TAAR1 Agonists as Potential Antipsychotic Drug Candidates

The existing available antipsychotics have failed to manage the cognitive impairment of schizophrenia and induced a number of seriously undesirable effects. Trace amine-associated receptor 1 (TAAR1) has emerged as an ideal target for the design of antischizophrenia drugs, with the ability to mediate multiple psychological functions by sensing endogenous amine-containing metabolites without the side effects of catalepsy. In this work, a series of novel TAAR1 agonists were designed based on the structural analysis of the TAAR1 activation pocket. Among them, 6e displayed a potent TAAR1-Gs/Gq dual-pathway activation property, being different from that of the clinical drug candidate SEP-363856 with only TAAR1-Gs pathway activation. In rodent models, 6e significantly alleviated MK-801-induced schizophrenia-like cognitive phenotypes without inducing catalepsy. Furthermore, 6e·HCl exhibited favorable pharmacokinetic (T1/2 = 2.31 h, F = 39%) and safety properties. All these demonstrated that 6e·HCl may be used as a novel drug candidate for schizophrenia treatment

Structure-Based Design of Novel G‑Protein-Coupled Receptor TAAR1 Agonists as Potential Antipsychotic Drug Candidates

The existing available antipsychotics have failed to manage the cognitive impairment of schizophrenia and induced a number of seriously undesirable effects. Trace amine-associated receptor 1 (TAAR1) has emerged as an ideal target for the design of antischizophrenia drugs, with the ability to mediate multiple psychological functions by sensing endogenous amine-containing metabolites without the side effects of catalepsy. In this work, a series of novel TAAR1 agonists were designed based on the structural analysis of the TAAR1 activation pocket. Among them, 6e displayed a potent TAAR1-Gs/Gq dual-pathway activation property, being different from that of the clinical drug candidate SEP-363856 with only TAAR1-Gs pathway activation. In rodent models, 6e significantly alleviated MK-801-induced schizophrenia-like cognitive phenotypes without inducing catalepsy. Furthermore, 6e·HCl exhibited favorable pharmacokinetic (T1/2 = 2.31 h, F = 39%) and safety properties. All these demonstrated that 6e·HCl may be used as a novel drug candidate for schizophrenia treatment

Structure-Based Design of Novel G‑Protein-Coupled Receptor TAAR1 Agonists as Potential Antipsychotic Drug Candidates

The existing available antipsychotics have failed to manage the cognitive impairment of schizophrenia and induced a number of seriously undesirable effects. Trace amine-associated receptor 1 (TAAR1) has emerged as an ideal target for the design of antischizophrenia drugs, with the ability to mediate multiple psychological functions by sensing endogenous amine-containing metabolites without the side effects of catalepsy. In this work, a series of novel TAAR1 agonists were designed based on the structural analysis of the TAAR1 activation pocket. Among them, 6e displayed a potent TAAR1-Gs/Gq dual-pathway activation property, being different from that of the clinical drug candidate SEP-363856 with only TAAR1-Gs pathway activation. In rodent models, 6e significantly alleviated MK-801-induced schizophrenia-like cognitive phenotypes without inducing catalepsy. Furthermore, 6e·HCl exhibited favorable pharmacokinetic (T1/2 = 2.31 h, F = 39%) and safety properties. All these demonstrated that 6e·HCl may be used as a novel drug candidate for schizophrenia treatment

Structure-Based Design of Novel G‑Protein-Coupled Receptor TAAR1 Agonists as Potential Antipsychotic Drug Candidates

The existing available antipsychotics have failed to manage the cognitive impairment of schizophrenia and induced a number of seriously undesirable effects. Trace amine-associated receptor 1 (TAAR1) has emerged as an ideal target for the design of antischizophrenia drugs, with the ability to mediate multiple psychological functions by sensing endogenous amine-containing metabolites without the side effects of catalepsy. In this work, a series of novel TAAR1 agonists were designed based on the structural analysis of the TAAR1 activation pocket. Among them, 6e displayed a potent TAAR1-Gs/Gq dual-pathway activation property, being different from that of the clinical drug candidate SEP-363856 with only TAAR1-Gs pathway activation. In rodent models, 6e significantly alleviated MK-801-induced schizophrenia-like cognitive phenotypes without inducing catalepsy. Furthermore, 6e·HCl exhibited favorable pharmacokinetic (T1/2 = 2.31 h, F = 39%) and safety properties. All these demonstrated that 6e·HCl may be used as a novel drug candidate for schizophrenia treatment

Structure-Based Design of Novel G‑Protein-Coupled Receptor TAAR1 Agonists as Potential Antipsychotic Drug Candidates

The existing available antipsychotics have failed to manage the cognitive impairment of schizophrenia and induced a number of seriously undesirable effects. Trace amine-associated receptor 1 (TAAR1) has emerged as an ideal target for the design of antischizophrenia drugs, with the ability to mediate multiple psychological functions by sensing endogenous amine-containing metabolites without the side effects of catalepsy. In this work, a series of novel TAAR1 agonists were designed based on the structural analysis of the TAAR1 activation pocket. Among them, 6e displayed a potent TAAR1-Gs/Gq dual-pathway activation property, being different from that of the clinical drug candidate SEP-363856 with only TAAR1-Gs pathway activation. In rodent models, 6e significantly alleviated MK-801-induced schizophrenia-like cognitive phenotypes without inducing catalepsy. Furthermore, 6e·HCl exhibited favorable pharmacokinetic (T1/2 = 2.31 h, F = 39%) and safety properties. All these demonstrated that 6e·HCl may be used as a novel drug candidate for schizophrenia treatment

Discovery of Novel Aryl Triazolone Dihydropyridines (ATDPs) Targeting Highly Conserved Residue W229 as Promising HIV‑1 NNRTIs

NNRTI is an important component of the highly active antiretroviral therapy (HAART), but the rapid emergence of drug resistance and poor pharmacokinetics limited their clinical application. Herein, a series of novel aryl triazolone dihydropyridines (ATDPs) were designed by structure-guided design with the aim of improving drug resistance profiles and pharmacokinetic profiles. Compound 10n (EC50 = 0.009–17.7 μM) exhibited the most active potency, being superior to or comparable to that of doravirine (DOR) against the whole tested viral panel. Molecular docking was performed to clarify the reason for its higher resistance profiles. Moreover, 10n demonstrated excellent pharmacokinetic profile (T1/2 = 5.09 h, F = 108.96%) compared that of DOR (T1/2 = 4.4 h, F = 57%). Additionally, 10n was also verified to have no in vivo acute or subacute toxicity (LD50 > 2000 mg/kg), suggesting that 10n is worth further investigation as a novel oral NNRTIs for HIV-1 therapy

Discovery of Novel Aryl Triazolone Dihydropyridines (ATDPs) Targeting Highly Conserved Residue W229 as Promising HIV‑1 NNRTIs

NNRTI is an important component of the highly active antiretroviral therapy (HAART), but the rapid emergence of drug resistance and poor pharmacokinetics limited their clinical application. Herein, a series of novel aryl triazolone dihydropyridines (ATDPs) were designed by structure-guided design with the aim of improving drug resistance profiles and pharmacokinetic profiles. Compound 10n (EC50 = 0.009–17.7 μM) exhibited the most active potency, being superior to or comparable to that of doravirine (DOR) against the whole tested viral panel. Molecular docking was performed to clarify the reason for its higher resistance profiles. Moreover, 10n demonstrated excellent pharmacokinetic profile (T1/2 = 5.09 h, F = 108.96%) compared that of DOR (T1/2 = 4.4 h, F = 57%). Additionally, 10n was also verified to have no in vivo acute or subacute toxicity (LD50 > 2000 mg/kg), suggesting that 10n is worth further investigation as a novel oral NNRTIs for HIV-1 therapy

Discovery of Novel Aryl Triazolone Dihydropyridines (ATDPs) Targeting Highly Conserved Residue W229 as Promising HIV‑1 NNRTIs

NNRTI is an important component of the highly active antiretroviral therapy (HAART), but the rapid emergence of drug resistance and poor pharmacokinetics limited their clinical application. Herein, a series of novel aryl triazolone dihydropyridines (ATDPs) were designed by structure-guided design with the aim of improving drug resistance profiles and pharmacokinetic profiles. Compound 10n (EC50 = 0.009–17.7 μM) exhibited the most active potency, being superior to or comparable to that of doravirine (DOR) against the whole tested viral panel. Molecular docking was performed to clarify the reason for its higher resistance profiles. Moreover, 10n demonstrated excellent pharmacokinetic profile (T1/2 = 5.09 h, F = 108.96%) compared that of DOR (T1/2 = 4.4 h, F = 57%). Additionally, 10n was also verified to have no in vivo acute or subacute toxicity (LD50 > 2000 mg/kg), suggesting that 10n is worth further investigation as a novel oral NNRTIs for HIV-1 therapy

Discovery of Novel Aryl Triazolone Dihydropyridines (ATDPs) Targeting Highly Conserved Residue W229 as Promising HIV‑1 NNRTIs

NNRTI is an important component of the highly active antiretroviral therapy (HAART), but the rapid emergence of drug resistance and poor pharmacokinetics limited their clinical application. Herein, a series of novel aryl triazolone dihydropyridines (ATDPs) were designed by structure-guided design with the aim of improving drug resistance profiles and pharmacokinetic profiles. Compound 10n (EC50 = 0.009–17.7 μM) exhibited the most active potency, being superior to or comparable to that of doravirine (DOR) against the whole tested viral panel. Molecular docking was performed to clarify the reason for its higher resistance profiles. Moreover, 10n demonstrated excellent pharmacokinetic profile (T1/2 = 5.09 h, F = 108.96%) compared that of DOR (T1/2 = 4.4 h, F = 57%). Additionally, 10n was also verified to have no in vivo acute or subacute toxicity (LD50 > 2000 mg/kg), suggesting that 10n is worth further investigation as a novel oral NNRTIs for HIV-1 therapy