Optimization of metabolic stability as a goal of modern drug design

Medicinal Research Reviews

Volumn 21, Issue 5, 2001, Pages 412-449

  Thompson, Thomas N ^a  

^a IQVIA   (United States)

Author keywords

DMPK; Drug design; Drug metabolism; Early ADME; Metabolic stability

Indexed keywords

AMIDASE; ANANDAMIDE; BENZIMIDAZOLE DERIVATIVE; CYTOCHROME P450; CYTOCHROME P450 2C9; CYTOCHROME P450 2D6; CYTOCHROME P450 3A; ENDOTHELIN RECEPTOR ANTAGONIST; ESTERASE; FATTY ACID DERIVATIVE; HYDROXYUREA; LACTONE DERIVATIVE; LIPOXYGENASE INHIBITOR; N ACETYL 10,11 DIHYDRO 5H DIBENZO[A,D]CYCLOHEPTEN 5 YLGLYCYLLEUCYLASPARTYLISOLEUCYLISOLEUCYLTRYPTOPHAN; NEW DRUG; NICOTINIC RECEPTOR; OXIDOREDUCTASE; OXYTOCIN ANTAGONIST; PD 156252; PROTEINASE INHIBITOR; RNA DIRECTED DNA POLYMERASE INHIBITOR; SEROTONIN 1A AGONIST; UNCLASSIFIED DRUG;

AEROBIC METABOLISM; CONFERENCE PAPER; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG CONFORMATION; DRUG CONJUGATION; DRUG DESIGN; DRUG DISTRIBUTION; DRUG EXCRETION; DRUG HALF LIFE; DRUG HYDROLYSIS; DRUG METABOLISM; ENZYME SPECIFICITY; IONIZATION; LIPOPHILICITY; LIVER MICROSOME;

AMIDOHYDROLASES; ANIMALS; DRUG DESIGN; ESTERASES; HUMANS; HYDROLYSIS; METABOLIC CLEARANCE RATE; OXIDATION-REDUCTION; PHARMACEUTICAL PREPARATIONS; SUBSTRATE SPECIFICITY;

EID: 0034890106     PISSN: 01986325     EISSN: None     Source Type: Journal    
DOI: 10.1002/med.1017     Document Type: Conference Paper

References (83)

1. Optimalization of pharmacokinetics - An essential aspect of drug development by "metabolic stabilization"
2. Drug metabolism and pharmacokinetics: Implications for drug design
3. Role of metabolism and pharmacokinetic studies in the discovery of new drugs - Present and future perspectives
4. The use of in vitro metabolism studies in the understanding of new drugs
5. Design of drugs through a consideration of drug metabolism and pharmacokinetics
6. Design of drugs involving the concepts and theories of drug metabolism and pharmacokinetics
7. Role of pharmacokinetics and metabolism in drug discovery and development
8. Early ADME in support of drug discovery: The role of metabolic stability studies
9. High-throughput screening in drug metabolism and pharmacokinetic support of drug discovery
10. Advances in in vitro drug metabolism screening
11. Pharmaceutical innovation by the seven UK-owned pharmaceutical companies
12. Drug discovery and drug metabolism
13. Selecting leads with pharmacokinetic data
14. Preclinical drug metabolism in the age of high-throughput screening: An industrial perspective
15. Rational high-throughput screening in preclinical drug metabolism
16. High-throughput approaches for evaluating absorption distribution, metabolism and excretion properties of lead compounds
17. The use of in vitro metabolism techniques in the planning and interpretation of drug safety studies
18. An overview of current cytochrome P450 technology for assessing the safety and efficacy of new materials
19. Increasing the throughput of microsomal stability screening using fast gradient elution LC/MS
20. A strategy for achieving higher throughput in screening for metabolic stability
21. Development of an automated mass spectrometry system for the quantitative analysis of liver microsomal incubation samples: A tool for rapid screening of new compounds for metabolic stability
22. Prediction of hepatic extraction ratio from in vitro measurements of intrinsic clearance
23. Utility of in vitro drug metabolism data in predicting in vivo metabolic clearance
24. Prediction of hepatic clearance from microsomes, hepatocytes, and liver slices
25. Quantitative prediction of in vivo drug clearance and drug interactions from in vitro data on metabolism, together with binding and transport
26. Prediction of in vivo drug metabolism in the human liver from in vitro metabolism data
27. The use of human hepatocytes to select compounds based on their expected hepatic extraction ratios in humans
28. The prediction of human pharmacokinetic parameters from preclinical and in vitro metabolism data
29. Speculations on the substrate structure-activity relationship (SSAR) of cytochrome P450 enzymes
30. Properties of cytochrome P450 isoenzymes and their substrates Part 1: Active site characteristics
31. Properties of cytochrome P450 isoenzymes and their substrates Part 2: Properties of cytochrome P450 substrates
32. Mechanisms of cytochrome P450 catalysis
33. Synthetic strategies to lower affinity for CYP2D6
34. Novel approach to predicting P450-mediated drug metabolism: Development of a combined protein and pharmacophore model for CYP2D6
35. A novel approach to predicting P450 mediated drug metabolism. CYP2D6 catalyzed N-dealkylation reactions and qualitative metabolite predictions using a combined protein and pharmacophore model for CYP2D6
36. Three- and four-dimensional quantitative structure activity relationship analyses of cytochrome P-4503A4 inhibitors
37. Three-dimensional-quantitative structure activity relationship analysis of cytochrome P-450 3A4 substrates
38. Putative active site template model for cytochrome P4502C9 (tolbutamide hydroxylase)
39. Three-dimensional quantitative structure activity relationship analyses of substrates for CYP2B6
40. 5 binding site and comparisons with CYP2B1 and CYP2B4
41. Hydrolysis of carbonates, thiocarbonates, carbamates, and carboxylic esters of α-naphthol, β-naphthol, and p-nitrophenol by human, rat, and mouse liver carboxylesterases
42. Biotransformation of xenobiotics
43. 2
44. Application of oral bioavailability surrogates in the design of orally active inhibitors of rhinovirus replication
45. Synthesis, antiviral activity, and biological properties of vinylacetylene analogs of enviroxime
46. Dioxabicyclooctanyl naphthalenenitriles as nonredox 5-lipoxygenase inhibitors: Structure-activity relationship study directed toward the improvement of metabolic stability
47. Discovery of ritonavir, a potent inhibitor of HIV protease with high oral bioavailability and clinical efficacy
48. Synthesis and bioactivity of novel bis (heteroaryl) piperazine (BHAP) reverse transcriptase inhibitors: Structure-activity relationships and increased metabolic stability of novel substituted pyridine analogs
49. Development of orally active oxytocin antagonists: Studies on 1-(1-[4-[ 1-(2-methyl-1-oxidopyridin-3-ylmethyl)piperidin-4-yloxy]-2-methoxybenzoyl] piperidin-4-yl)-1,4-dihydrobenz[d][1,3]oxazin-2-one (L-372,662) and related pyridines
50. Structure-activity studies on 2-methyl-3-(2(S)-pyrrolidinylmethoxy) pyridine (ABT-089): An orally bioavailable 3-pyridyl ether nicotinic acetylcholine receptor ligand with cognition-enhancing properties
51. In vitro stability and intestinal absorption characteristics of hexapeptide endothelin receptor antagonists
52. Novel analogues of arachidonylethanolamide (anandamide): Affinities for the CB1 and CB2 cannabinoid receptors and metabolic stability
53. 1A receptor ligands
54. Improving the in vivo duration of 5-lipoxygenase inhibitors application of an in vitro glucuronosyltransferase assay
55. Structure-activity relationships of N-hydroxyurea 5-lipoxygenase inhibitors
56. Metabolic screening using on-line ultrafiltration mass spectrometry
57. Use of liquid chromatography/mass spectrometry for rapid metabolite screens during drug discovery
58. HPLC-API/MS/MS: A powerful tool for integrating drug metabolism into the drug discovery process
59. High-throughput high-performance liquid chromatography/mass spectrometry for modern drug discovery
60. Development of an automatible, high-throughput method for rapid analysis of drug metabolism
61. Electrochemiluminescence-based quantitation of classical clinical chemistry analytes
62. Quantitative structure-activity relationships of cytochrome P-450
63. Structural characteristics of human P450s involved in drug metabolism: QSARs and lipophilicity profiles
64. On the recognition of mammalian microsomal cytochrome P450 substrates and their characteristics: Towards the prediction of human p450 substrate specificity and metabolism
65. MetabolExpert: Its use in metabolism research and development and in combinatorial chemistry
66. Meta: A program for the prediction of the products of mammal metabolism of xenobiotics
67. Metabolite
68. Synopsis' metabolism database
69. Use and value of metabolism databases
70. Mining structure-metabolism relationships from the MDL "Metabolite" database
71. Predicting the regioselectivity and stereoselectivity of cytochrome P450-mediated reactions: Structural models for bioactivation reactions
72. Structure-function of cytochromes P450 and flavin-containing monooxygenases: Implications for drug metabolism
73. Electronic models for cytochrome P450 oxidations
74. Computational methods for the prediction of "drug"-likeness"
75. QSAR model for drug human oral bioavailability
76. Predicting human oral bioavailability of a compound: Development of a novel quantitative structure-bioavailability relationship
77. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings
78. Three-dimensional quantitative structure activity relationship computational approaches for prediction of human in vitro intrinsic clearance
79. Prediction of human clearance of twenty-nine drugs from hepatic microsomal intrinsic clearance data: An examination of in vitro half-life approach and nonspecific binding to microsomes
80. A case study: Selection of a diversified set of compounds for in vitro profiling for validation testing using the IDEA™ predictive model
81. Computational models to predict ADME characteristics of drug candidates