LEADER 06480nam 22007215 450 001 9910298633703321 005 20200630172448.0 010 $a3-642-55041-X 024 7 $a10.1007/978-3-642-55041-6 035 $a(CKB)3710000000315886 035 $a(EBL)1968168 035 $a(SSID)ssj0001408017 035 $a(PQKBManifestationID)11967307 035 $a(PQKBTitleCode)TC0001408017 035 $a(PQKBWorkID)11412575 035 $a(PQKB)11628456 035 $a(DE-He213)978-3-642-55041-6 035 $a(MiAaPQ)EBC1968168 035 $a(PPN)18315357X 035 $a(EXLCZ)993710000000315886 100 $a20141208d2015 u| 0 101 0 $aeng 135 $aur|n|---||||| 181 $ctxt 182 $cc 183 $acr 200 10$aTactics in Contemporary Drug Design /$fedited by Nicholas A. Meanwell 205 $a1st ed. 2015. 210 1$aBerlin, Heidelberg :$cSpringer Berlin Heidelberg :$cImprint: Springer,$d2015. 215 $a1 online resource (400 p.) 225 1 $aTopics in Medicinal Chemistry,$x1862-2461 ;$v12 300 $aDescription based upon print version of record. 311 $a3-642-55040-1 320 $aIncludes bibliographical references and index. 327 $aPreface to the Series; Preface; Contents; Physical Properties in Drug Design; 1 Introduction: The Realisation of Physical Property Issues; 1.1 Molecular Obesity and Obsession with Potency; 1.2 Med Chem Inflates Properties: The Body Doesn´t Change; 2 Physical Properties: What Are They and Which Are Important?; 2.1 Lipophilicity/Hydrophobicity; 2.1.1 Small Hydrophilic Molecules: A Forgotten Strategy for Oral Medicines?; 2.1.2 Methods for the Measurement and Prediction of Lipophilicity; 2.1.3 Octanol Water Methods: Issues with Overly Lipophilic Compounds 327 $a2.1.4 Measurements Using Chromatographic Methods2.2 Acid/Base Strength: pKa; 2.2.1 Measurement and Calculation of pKa; 2.3 Solubility; 2.3.1 The General Solubility Equation; 2.3.2 Simulated Gastrointestinal Fluids; 2.4 Escape from Flatland and the Impact of Aromatic Ring Count; 2.4.1 Lipophilicity and Aromaticity Act in Unison; 3 How the Physical Environment of a Drug Changes from Administration to Target; 3.1 The Passage Through the Body for an Oral Medicine; 3.2 Oral Developability Classification System: Dose, Solubility and Permeation 327 $a4 Impact of Physical Properties on Developability and DMPK Parameters4.1 General Aspects of Lipophilicity-Dependent Behaviour; 4.2 Impact of logP, logDpH and Aromaticity on Particular Parameters; 4.2.1 Permeability; 4.2.2 Cytochrome P450s; 4.2.3 hERG Binding; 4.2.4 Promiscuity; 4.2.5 Human Serum Albumin Binding; 4.2.6 Intrinsic Clearance; 4.3 The Composite Risks of Poor Physical Profiles; 5 Efficiency Metrics and Their Interrelationship with Physical Properties; 5.1 Drug Efficiency; 5.1.1 Physical Estimates of Drug Efficiency; 5.2 Ligand Efficiency and Related Measures 327 $a5.3 Ligand Lipophilicity Efficiency Measures5.4 The Combined Influence of Efficiency Metrics and Physical Property Measures; 5.5 The Thermodynamics of Efficient Binding; 6 Conclusions; References; Improving Solubility via Structural Modification; 1 Introduction; 2 Description of Aqueous Solubility; 2.1 Definition of Solubility; 2.2 General Solubility Equation; 2.3 Solvation of Organic Molecules; 2.3.1 Effect of Molecular Size and Shape on Solvation; 2.3.2 Water-Solute Hydrogen Bonding; 2.4 Crystal Lattice Stability and Packing Efficiency; 2.4.1 Effect of Molecular Shape on Packing Efficiency 327 $a2.4.2 Intermolecular Interactions in the Solid State2.4.3 The Effect of Molecular Symmetry on Crystal Packing; 3 Tactics for Improving Solubility; 3.1 Reducing LogP; 3.1.1 Introducing a Solubilizing Appendage; Introducing Basic Appendages; Introducing Acidic Appendages; Introduction of Neutral Appendages; 3.1.2 Template and Substituent Modifications; Substituent Modifications; Analysis of Substituent Effects on Solubility; The Dual Nature of Fluorine; Intramolecular Interactions; Examples of Substituent Modifications; Template Modifications; 3.2 Disrupting Crystal Lattice Stability 327 $a3.2.1 Disruption of Intermolecular H-Bonding Interactions 330 $aMedicinal chemistry is both science and art. The science of medicinal chemistry offers mankind one of its best hopes for improving the quality of life. The art of medicinal chemistry continues to challenge its practitioners with the need for both intuition and experience to discover new drugs. Hence sharing the experience of drug research is uniquely beneficial to the field of medicinal chemistry. Drug research requires interdisciplinary team-work at the interface between chemistry, biology and medicine. Therefore, the topic-related series Topics in Medicinal Chemistry covers all relevant aspects of drug research, e.g. pathobiochemistry of diseases, identification and validation of (emerging) drug targets, structural biology, drugability of targets, drug design approaches, chemogenomics, synthetic chemistry including combinatorial methods, bioorganic chemistry, natural compounds, high-throughput screening, pharmacological in vitro and in vivo investigations, drug-receptor interactions on the molecular level, structure-activity relationships, drug absorption, distribution, metabolism, elimination, toxicology and pharmacogenomics. In general, special volumes are edited by well known guest editors. 410 0$aTopics in Medicinal Chemistry,$x1862-2461 ;$v12 606 $aMedicinal chemistry 606 $aMolecular biology 606 $aPharmacology 606 $aMedicinal Chemistry$3https://scigraph.springernature.com/ontologies/product-market-codes/C28000 606 $aMolecular Medicine$3https://scigraph.springernature.com/ontologies/product-market-codes/B1700X 606 $aPharmacology/Toxicology$3https://scigraph.springernature.com/ontologies/product-market-codes/B21007 615 0$aMedicinal chemistry. 615 0$aMolecular biology. 615 0$aPharmacology. 615 14$aMedicinal Chemistry. 615 24$aMolecular Medicine. 615 24$aPharmacology/Toxicology. 676 $a54 676 $a611.01816 676 $a615 676 $a615.19 702 $aMeanwell$b Nicholas A$4edt$4http://id.loc.gov/vocabulary/relators/edt 906 $aBOOK 912 $a9910298633703321 996 $aTactics in Contemporary Drug Design$92007745 997 $aUNINA