The Experts below are selected from a list of 14814 Experts worldwide ranked by ideXlab platform
Yuxiang Dong - One of the best experts on this subject based on the ideXlab platform.
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revisiting the sar of the antischistosomal aryl hydantoin ro 13 3978
Journal of Medicinal Chemistry, 2016Co-Authors: Chunkai Wang, Qingjie Zhao, Mireille Vargas, Jeremy O Jones, Karen L White, David M Shackleford, Gong Chen, Jessica Saunders, Francis C K Chiu, Yuxiang DongAbstract:The aryl hydantoin 1 (Ro 13-3978) was identified in the early 1980s as a promising antischistosomal lead compound. However, this series of aryl hydantoins produced antiandrogenic side effects in the host, a not unexpected outcome given their close structural similarity to the antiandrogenic drug nilutamide. Building on the known SAR of this compound series, we now describe a number of analogs of 1 designed to maximize structural diversity guided by incorporation of substructures and functional groups known to diminish ligand–androgen receptor interactions. These analogs had calculated Polar Surface Area (PSA), measured LogD7.4, aqueous kinetic solubility, and estimated plasma protein binding values in ranges predictive of good ADME profiles. The principal SAR insight was that the hydantoin core of 1 is required for high antischistosomal activity. We identified several compounds with high antischistosomal efficacy that were less antiandrogenic than 1. These data provide direction for the ongoing optimizati...
Chunkai Wang - One of the best experts on this subject based on the ideXlab platform.
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revisiting the sar of the antischistosomal aryl hydantoin ro 13 3978
Journal of Medicinal Chemistry, 2016Co-Authors: Chunkai Wang, Qingjie Zhao, Mireille Vargas, Jeremy O Jones, Karen L White, David M Shackleford, Gong Chen, Jessica Saunders, Francis C K Chiu, Yuxiang DongAbstract:The aryl hydantoin 1 (Ro 13-3978) was identified in the early 1980s as a promising antischistosomal lead compound. However, this series of aryl hydantoins produced antiandrogenic side effects in the host, a not unexpected outcome given their close structural similarity to the antiandrogenic drug nilutamide. Building on the known SAR of this compound series, we now describe a number of analogs of 1 designed to maximize structural diversity guided by incorporation of substructures and functional groups known to diminish ligand–androgen receptor interactions. These analogs had calculated Polar Surface Area (PSA), measured LogD7.4, aqueous kinetic solubility, and estimated plasma protein binding values in ranges predictive of good ADME profiles. The principal SAR insight was that the hydantoin core of 1 is required for high antischistosomal activity. We identified several compounds with high antischistosomal efficacy that were less antiandrogenic than 1. These data provide direction for the ongoing optimizati...
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Revisiting the SAR of the Antischistosomal Aryl Hydantoin (Ro 13-3978)
2016Co-Authors: Chunkai Wang, Qingjie Zhao, Mireille Vargas, Jeremy O Jones, Karen L White, David M Shackleford, Gong Chen, Jessica Saunders, Francis C K ChiuAbstract:The aryl hydantoin 1 (Ro 13-3978) was identified in the early 1980s as a promising antischistosomal lead compound. However, this series of aryl hydantoins produced antiandrogenic side effects in the host, a not unexpected outcome given their close structural similarity to the antiandrogenic drug nilutamide. Building on the known SAR of this compound series, we now describe a number of analogs of 1 designed to maximize structural diversity guided by incorporation of substructures and functional groups known to diminish ligand–androgen receptor interactions. These analogs had calculated Polar Surface Area (PSA), measured LogD7.4, aqueous kinetic solubility, and estimated plasma protein binding values in ranges predictive of good ADME profiles. The principal SAR insight was that the hydantoin core of 1 is required for high antischistosomal activity. We identified several compounds with high antischistosomal efficacy that were less antiandrogenic than 1. These data provide direction for the ongoing optimization of antischistosomal hydantoins
Milan Remko - One of the best experts on this subject based on the ideXlab platform.
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A Comparative Study of Molecular Structure, pKa, Lipophilicity, Solubility, Absorption and Polar Surface Area of Some Antiplatelet Drugs
International journal of molecular sciences, 2016Co-Authors: Milan Remko, Anna Remková, Ria BroerAbstract:Theoretical chemistry methods have been used to study the molecular properties of antiplatelet agents (ticlopidine, clopidogrel, prasugrel, elinogrel, ticagrelor and cangrelor) and several thiol-containing active metabolites. The geometries and energies of most stable conformers of these drugs have been computed at the Becke3LYP/6-311++G(d,p) level of density functional theory. Computed dissociation constants show that the active metabolites of prodrugs (ticlopidine, clopidogrel and prasugrel) and drugs elinogrel and cangrelor are completely ionized at pH 7.4. Both ticagrelor and its active metabolite are present at pH = 7.4 in neutral undissociated form. The thienopyridine prodrugs ticlopidine, clopidogrel and prasugrel are lipophilic and insoluble in water. Their lipophilicity is very high (about 2.5–3.5 logP values). The Polar Surface Area, with regard to the structurally-heterogeneous character of these antiplatelet drugs, is from very large interval of values of 3–255 A2. Thienopyridine prodrugs, like ticlopidine, clopidogrel and prasugrel, with the lowest Polar Surface Area (PSA) values, exhibit the largest absorption. A high value of Polar Surface Area (PSA) of cangrelor (255 A2) results in substantial worsening of the absorption in comparison with thienopyridine drugs.
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a comparative study of the molecular structure lipophilicity solubility acidity absorption and Polar Surface Area of coumarinic anticoagulants and direct thrombin inhibitors
RSC Advances, 2014Co-Authors: Milan Remko, Ria Broer, Anna RemkováAbstract:The methods of computational chemistry have been used to elucidate the molecular properties of coumarinic anticoagulants (acenocoumarol, phenprocoumon, warfarin and tecarfarin) and direct thrombin inhibitors (melagatran, dabigatran and their prodrug forms, ximelagatran and dabigatran etexilate). The geometries and energies of these drugs have been computed at the Becke3LYP/6-311++G(d,p) level of theory. In the case of the vitamin K antagonists (acenocoumarol, phenprocoumon, warfarin and tecarfarin), the most stable tautomer in both the gas-phase and water solution is tautomer A, which contains the 4-hydroxycoumarin moiety. The R(+)-enantiomer of this tautomer is the most stable structure in warfarin and acetocoumarol. For phenprocoumon, the S(−)-enantiomer was the most stable species. The computed dissociation constants show that these drugs are almost completely ionized at physiological pH = 7.4. Tecarfarin is the vitamin K antagonist with the highest lipophilicity. The prodrugs ximelagatran and dabigatran etexilate are described as lipophilic drugs. The prodrugs' metabolites, melagatran and dabigatran, are substantially less lipophilic. The relatively high Polar Surface Area value of acenocoumarol (113.3) results in lessened absorption in comparison with warfarin. Phenprocoumon, with PSA value 50.4, had the highest calculated absorption of all of the anticoagulants in the study. The direct thrombin inhibitors, melagatran and dabigatran, have a high total number of proton donor and proton acceptor groups (15), a high PSA (150) and the lowest absorption of the drugs studied.
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theoretical study of molecular structure pka lipophilicity solubility absorption and Polar Surface Area of some hypoglycemic agents
Journal of Molecular Structure-theochem, 2009Co-Authors: Milan RemkoAbstract:Abstract The methods of theoretical chemistry have been used to elucidate molecular properties of the hypoglycemic sulfonylureas and glinides (acetohexamide, tofazamide, tolbutamide, chlorpropamide, gliclazide, glimepiride, glipizide, glibenclamide, nateglinide, and repaglinide). The geometries and energies of these drugs have been computed using HF/6-31G(d) and Becke3LYP/6-31G(d) methods. The equilibrium structure of the sulfonylureas investigated in the isolated state is determined by the formation of suitable intramolecular hydrogen bonds within the sulfonamide moiety. This specific interaction gives rise to the unique overall shape of individual drug conformers. Values of these dihedral angles for individual drugs are different. Generally, the ab initio SCF and DFT optimized structures in the gas phase fit well one another. Water has a remarkable effect on the geometry of the drugs studied. The p K a values of sulfonylurea moiety are in the range of 5.2–6.2 and these drugs are characterized as weak organic acids. Repaglinide and nateglinide are oral blood glucose-lowering drugs of the glinide class containing acidic carboxylic group. The p K a values of this carboxylic acid moiety are in the range of 3.5–4.0. Computed partition coefficients (XLOGP2 method) for drugs studied varied between 1.8 and 5.9. Thus these compounds are described as lipophilic drugs. Although the sulfonylurea and glinidine derivatives studied are only slightly soluble in water, their computed solubilities from interval between 0.001 and 4 g/L are sufficient for fast adsorption.
Francis C K Chiu - One of the best experts on this subject based on the ideXlab platform.
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revisiting the sar of the antischistosomal aryl hydantoin ro 13 3978
Journal of Medicinal Chemistry, 2016Co-Authors: Chunkai Wang, Qingjie Zhao, Mireille Vargas, Jeremy O Jones, Karen L White, David M Shackleford, Gong Chen, Jessica Saunders, Francis C K Chiu, Yuxiang DongAbstract:The aryl hydantoin 1 (Ro 13-3978) was identified in the early 1980s as a promising antischistosomal lead compound. However, this series of aryl hydantoins produced antiandrogenic side effects in the host, a not unexpected outcome given their close structural similarity to the antiandrogenic drug nilutamide. Building on the known SAR of this compound series, we now describe a number of analogs of 1 designed to maximize structural diversity guided by incorporation of substructures and functional groups known to diminish ligand–androgen receptor interactions. These analogs had calculated Polar Surface Area (PSA), measured LogD7.4, aqueous kinetic solubility, and estimated plasma protein binding values in ranges predictive of good ADME profiles. The principal SAR insight was that the hydantoin core of 1 is required for high antischistosomal activity. We identified several compounds with high antischistosomal efficacy that were less antiandrogenic than 1. These data provide direction for the ongoing optimizati...
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Revisiting the SAR of the Antischistosomal Aryl Hydantoin (Ro 13-3978)
2016Co-Authors: Chunkai Wang, Qingjie Zhao, Mireille Vargas, Jeremy O Jones, Karen L White, David M Shackleford, Gong Chen, Jessica Saunders, Francis C K ChiuAbstract:The aryl hydantoin 1 (Ro 13-3978) was identified in the early 1980s as a promising antischistosomal lead compound. However, this series of aryl hydantoins produced antiandrogenic side effects in the host, a not unexpected outcome given their close structural similarity to the antiandrogenic drug nilutamide. Building on the known SAR of this compound series, we now describe a number of analogs of 1 designed to maximize structural diversity guided by incorporation of substructures and functional groups known to diminish ligand–androgen receptor interactions. These analogs had calculated Polar Surface Area (PSA), measured LogD7.4, aqueous kinetic solubility, and estimated plasma protein binding values in ranges predictive of good ADME profiles. The principal SAR insight was that the hydantoin core of 1 is required for high antischistosomal activity. We identified several compounds with high antischistosomal efficacy that were less antiandrogenic than 1. These data provide direction for the ongoing optimization of antischistosomal hydantoins
Peter Ertl - One of the best experts on this subject based on the ideXlab platform.
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fast calculation of molecular Polar Surface Area as a sum of fragment based contributions and its application to the prediction of drug transport properties
Journal of Medicinal Chemistry, 2000Co-Authors: Peter Ertl, Bernhard Rohde, Paul M SelzerAbstract:Molecular Polar Surface Area (PSA), i.e., Surface belonging to Polar atoms, is a descriptor that was shown to correlate well with passive molecular transport through membranes and, therefore, allows prediction of transport properties of drugs. The calculation of PSA, however, is rather time-consuming because of the necessity to generate a reasonable 3D molecular geometry and the calculation of the Surface itself. A new approach for the calculation of the PSA is presented here, based on the summation of tabulated Surface contributions of Polar fragments. The method, termed topological PSA (TPSA), provides results which are practically identical with the 3D PSA (the correlation coefficient between 3D PSA and fragment-based TPSA for 34 810 molecules from the World Drug Index is 0.99), while the computation speed is 2−3 orders of magnitude faster. The new methodology may, therefore, be used for fast bioavailability screening of virtual libraries having millions of molecules. This article describes the new met...
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fast calculation of molecular Polar Surface Area as a sum of fragment based contributions and its application to the prediction of drug transport properties
Journal of Medicinal Chemistry, 2000Co-Authors: Peter Ertl, Bernhard Rohde, Paul SelzerAbstract:Molecular Polar Surface Area (PSA), i.e., Surface belonging to Polar atoms, is a descriptor that was shown to correlate well with passive molecular transport through membranes and, therefore, allows prediction of transport properties of drugs. The calculation of PSA, however, is rather time-consuming because of the necessity to generate a reasonable 3D molecular geometry and the calculation of the Surface itself. A new approach for the calculation of the PSA is presented here, based on the summation of tabulated Surface contributions of Polar fragments. The method, termed topological PSA (TPSA), provides results which are practically identical with the 3D PSA (the correlation coefficient between 3D PSA and fragment-based TPSA for 34 810 molecules from the World Drug Index is 0.99), while the computation speed is 2-3 orders of magnitude faster. The new methodology may, therefore, be used for fast bioavailability screening of virtual libraries having millions of molecules. This article describes the new methodology and shows the results of validation studies based on sets of published absorption data, including intestinal absorption, Caco-2 monolayer penetration, and blood-brain barrier penetration.