Structure Activity Relationship forms the basis of Rational Drug Design in the circles of pharmaceutical and medicinal chemistry. Appropriate knowledge of functional outcomes of structural modifications is crucial in ...Structure Activity Relationship forms the basis of Rational Drug Design in the circles of pharmaceutical and medicinal chemistry. Appropriate knowledge of functional outcomes of structural modifications is crucial in conferring desired pharmacological properties to a chemical compound. Amiodarone is a classical antiarrythmic agent with a long list of adverse effects. This article attempts to review the structure activity relationship of some of the homologues of amiodarone in order to determine the most clinically desirable molecule.展开更多
Brassinolide (BR) is a new potent growth promoting steroid substance which was first isolated from rape pollen by Grove et al. in 1979. Since then a number of BR analogues, such as homobrassinolide 2 and epibrassinoli...Brassinolide (BR) is a new potent growth promoting steroid substance which was first isolated from rape pollen by Grove et al. in 1979. Since then a number of BR analogues, such as homobrassinolide 2 and epibrassinolide 3, have been discovered in plant. Unnatural compounds with similar structure to brassinolide have展开更多
Drug optimization, which improves drug potency/specificity by structure-activity relationship(SAR) and drug-like properties, is rigorously performed to select drug candidates for clinical trials. However,the current d...Drug optimization, which improves drug potency/specificity by structure-activity relationship(SAR) and drug-like properties, is rigorously performed to select drug candidates for clinical trials. However,the current drug optimization may overlook the structure-tissue exposure/selectivity-relationship(STR) in disease-targeted tissues vs. normal tissues, which may mislead the drug candidate selection and impact the balance of clinical efficacy/toxicity. In this study, we investigated the STR in correlation with observed clinical efficacy/toxicity using seven selective estrogen receptor modulators(SERMs) that have similar structures, same molecular target, and similar/different pharmacokinetics. The results showed that drug’s plasma exposure was not correlated with drug’s exposures in the target tissues(tumor, fat pad, bone, uterus),while tissue exposure/selectivity of SERMs was correlated with clinical efficacy/safety. Slight structure modifications of four SERMs did not change drug’s plasma exposure but altered drug’s tissue exposure/selectivity.Seven SERMs with high protein binding showed higher accumulation in tumors compared to surrounding normal tissues, which is likely due to tumor EPR effect of protein-bound drugs. These suggest that STR alters drug’s tissue exposure/selectivity in disease-targeted tissues vs. normal tissues impacting clinical efficacy/toxicity. Drug optimization needs to balance the SAR and STR in selecting drug candidate for clinical trial to improve success of clinical drug development.展开更多
文摘Structure Activity Relationship forms the basis of Rational Drug Design in the circles of pharmaceutical and medicinal chemistry. Appropriate knowledge of functional outcomes of structural modifications is crucial in conferring desired pharmacological properties to a chemical compound. Amiodarone is a classical antiarrythmic agent with a long list of adverse effects. This article attempts to review the structure activity relationship of some of the homologues of amiodarone in order to determine the most clinically desirable molecule.
文摘Brassinolide (BR) is a new potent growth promoting steroid substance which was first isolated from rape pollen by Grove et al. in 1979. Since then a number of BR analogues, such as homobrassinolide 2 and epibrassinolide 3, have been discovered in plant. Unnatural compounds with similar structure to brassinolide have
基金partially supported by the funding from Celgene Corporation (USA)。
文摘Drug optimization, which improves drug potency/specificity by structure-activity relationship(SAR) and drug-like properties, is rigorously performed to select drug candidates for clinical trials. However,the current drug optimization may overlook the structure-tissue exposure/selectivity-relationship(STR) in disease-targeted tissues vs. normal tissues, which may mislead the drug candidate selection and impact the balance of clinical efficacy/toxicity. In this study, we investigated the STR in correlation with observed clinical efficacy/toxicity using seven selective estrogen receptor modulators(SERMs) that have similar structures, same molecular target, and similar/different pharmacokinetics. The results showed that drug’s plasma exposure was not correlated with drug’s exposures in the target tissues(tumor, fat pad, bone, uterus),while tissue exposure/selectivity of SERMs was correlated with clinical efficacy/safety. Slight structure modifications of four SERMs did not change drug’s plasma exposure but altered drug’s tissue exposure/selectivity.Seven SERMs with high protein binding showed higher accumulation in tumors compared to surrounding normal tissues, which is likely due to tumor EPR effect of protein-bound drugs. These suggest that STR alters drug’s tissue exposure/selectivity in disease-targeted tissues vs. normal tissues impacting clinical efficacy/toxicity. Drug optimization needs to balance the SAR and STR in selecting drug candidate for clinical trial to improve success of clinical drug development.
