The trend toward designing large hydrophobic molecules for lead optimization is often associated with poor drug-likeness and high attrition rates in drug discovery and development. Structural simplification is a power...The trend toward designing large hydrophobic molecules for lead optimization is often associated with poor drug-likeness and high attrition rates in drug discovery and development. Structural simplification is a powerful strategy for improving the efficiency and success rate of drug design by avoiding 'molecular obesity'. The structural simplification of large or complex lead compounds by truncating unnecessary groups can not only improve their synthetic accessibility but also improve their pharmacokinetic profiles, reduce side effects and so on. This review will summarize the application of structural simplification in lead optimization. Numerous case studies, particularly those involving successful examples leading to marketed drugs or drug-like candidates, will be introduced and analyzed to illustrate the design strategies and guidelines for structural simplification.展开更多
The structure–activity relationship（SAR） study of a 1 2 3 4 4a 9a-hexahydro-1H-xanthene series of selective,human glucocorticoid receptor a（hGRa） antagonists is reported.Compounds were screened using hydroxyapati...The structure–activity relationship（SAR） study of a 1 2 3 4 4a 9a-hexahydro-1H-xanthene series of selective,human glucocorticoid receptor a（hGRa） antagonists is reported.Compounds were screened using hydroxyapatite-based GR binding and MMTV-Luc co-transfection reporter gene assays.Four different regions of the scaffold were modified to assess the effects on hGRa antagonism and related potency.Compound 8d exhibits an 8-fold better bioactivity than the original hit 1a,as well as an improved chemical stability,which make it a promising lead for the subsequent optimization.展开更多
This paper deals with the problem of planned lead time calculation in a Material Requirement Planning （MRP） environment under stochastic lead times. The objective is to minimize the sum of holding and backlogging co...This paper deals with the problem of planned lead time calculation in a Material Requirement Planning （MRP） environment under stochastic lead times. The objective is to minimize the sum of holding and backlogging costs. The proposed approach is based on discrete time inventory control where the decision variables are integer. Two types of systems are considered： multi-level serial-production and assembly systems. For the serial production systems （one type of component at each level）, a mathematical model is suggested. Then, it is proven that this model is equivalent to the well known discrete Newsboy Model. This directly provides the optimal values for the planned lead times. For multilevel assembly systems, a dedicated model is proposed and some properties of the decision variables and objective function are proven. These properties are used to calculate lower and upper limits on the decision variables and lower and upper bounds on the objective function. The obtained limits and bounds open the possibility to develop an efficient optimization algorithm using, for example, a Branch and Bound approach. The paper presents the proposed models in detail with corresponding proofs and se＇~eral numerical examples. Some advantages of the suggested models and perspectives of this research are discussed.展开更多
基金supported by the National Natural Science Foundation of China (Grant No. 81725020 to Chunquan Sheng and No. 21602252 to Shengzheng Wang)the Innovation Program of Shanghai Municipal Education Commission (Grant No. 2019-0107-00-07-E00073 to Chunquan Sheng, China)the Hong Kong Scholars Program (Grant No. XJ201713 to Shengzheng Wang, China)
文摘The trend toward designing large hydrophobic molecules for lead optimization is often associated with poor drug-likeness and high attrition rates in drug discovery and development. Structural simplification is a powerful strategy for improving the efficiency and success rate of drug design by avoiding 'molecular obesity'. The structural simplification of large or complex lead compounds by truncating unnecessary groups can not only improve their synthetic accessibility but also improve their pharmacokinetic profiles, reduce side effects and so on. This review will summarize the application of structural simplification in lead optimization. Numerous case studies, particularly those involving successful examples leading to marketed drugs or drug-like candidates, will be introduced and analyzed to illustrate the design strategies and guidelines for structural simplification.
基金supported in part by grants from the Ministry of Health of China (Nos. 2012ZX09304-011, 2013ZX09401003-005, 2013ZX09507001 and 2013ZX09507002)Shanghai Science and Technology Development Fund (No. 13DZ2290300)Thousand Talents Program in China
文摘The structure–activity relationship（SAR） study of a 1 2 3 4 4a 9a-hexahydro-1H-xanthene series of selective,human glucocorticoid receptor a（hGRa） antagonists is reported.Compounds were screened using hydroxyapatite-based GR binding and MMTV-Luc co-transfection reporter gene assays.Four different regions of the scaffold were modified to assess the effects on hGRa antagonism and related potency.Compound 8d exhibits an 8-fold better bioactivity than the original hit 1a,as well as an improved chemical stability,which make it a promising lead for the subsequent optimization.
文摘This paper deals with the problem of planned lead time calculation in a Material Requirement Planning （MRP） environment under stochastic lead times. The objective is to minimize the sum of holding and backlogging costs. The proposed approach is based on discrete time inventory control where the decision variables are integer. Two types of systems are considered： multi-level serial-production and assembly systems. For the serial production systems （one type of component at each level）, a mathematical model is suggested. Then, it is proven that this model is equivalent to the well known discrete Newsboy Model. This directly provides the optimal values for the planned lead times. For multilevel assembly systems, a dedicated model is proposed and some properties of the decision variables and objective function are proven. These properties are used to calculate lower and upper limits on the decision variables and lower and upper bounds on the objective function. The obtained limits and bounds open the possibility to develop an efficient optimization algorithm using, for example, a Branch and Bound approach. The paper presents the proposed models in detail with corresponding proofs and se＇~eral numerical examples. Some advantages of the suggested models and perspectives of this research are discussed.
