Evaluation of dynamic polar molecular surface area as predictor of drug absorption: Comparison with other computational and experimental predictors

Journal of Medicinal Chemistry

Volumn 41, Issue 27, 1998, Pages 5382-5392

  Palm, Katrin ^a   Luthman, Kristina ^a   Ungell, Anna Lena ^a   Strandlund, Gert ^b   Beigi, Farideh ^a   Lundahl, Per ^c   Artursson, Per ^a  

^a UPPSALA UNIVERSITY   (Sweden)

^b ASTRAZENECA R AND D   (Sweden)

^c UNIVERSITY OF TROMSØ   (Norway)

Author keywords

[No Author keywords available]

Indexed keywords

ALPRENOLOL; ATENOLOL; BETA ADRENERGIC RECEPTOR BLOCKING AGENT; H 244 45; H 95 71; METOPROLOL; N [2 [3 [4 [2 (2 CYCLOPROPYLMETHOXYETHOXY)ETHYL]PHENOXY] 2 HYDROXYPROPYLAMINO]ETHYL] 4 HYDROXY 1 PIPERIDINECARBOXAMIDE; OXPRENOLOL; PINDOLOL; PRACTOLOL; UNCLASSIFIED DRUG;

ARTICLE; CONFORMATIONAL TRANSITION; DRUG ABSORPTION; DRUG CONFORMATION; HUMAN; HUMAN CELL; HYDROGEN BOND; INTESTINE ABSORPTION; INTESTINE MUCOSA PERMEABILITY; PREDICTION;

ADRENERGIC BETA-ANTAGONISTS; AMIDES; BIOLOGICAL TRANSPORT; CACO-2 CELLS; CHROMATOGRAPHY, LIQUID; DRUG DESIGN; EPITHELIAL CELLS; FORMAMIDES; HUMANS; INTESTINAL ABSORPTION; LIPOSOMES; MODELS, MOLECULAR; MOLECULAR CONFORMATION; MONTE CARLO METHOD; PERMEABILITY; PROPANOLAMINES; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 0032585545     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm980313t     Document Type: Article

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24. This is in contrast with results obtained by NMR spectroscopy in CDCla which indicate a 1:1 mixture of amide rotamers in H 95/71. This prevented a more detailed analysis of the spectra due to overlapping peaks. NMR spectra of H 244/45 were more informative indicating preferences for conformations stabilized by intramolecular hydrogen bonding between the amine and alcohol functionalities. No hydrogen bond stabilization involving the ether oxygen was identified. This is in contrast with the results from the Monte Carlo conformational search which gave low-energy conformations including both these hydrogen bonds to about the same extent.
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27. The low-energy conformations were divided into groups according to ref 18. The groups displayed different polar surface properties (0.001; ANOVA), and the variation within groups was small.
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