AbstractConsiderable effort has been devoted to the characterization of P‐glycoprotein — drug interaction in the past. Systematic quantitative structure‐activity relationship (QSAR) studies identified both predictive physicochemical parameters and pharmacophoric substructures within homologous series of compounds. Comparative molecular field analysis (CoMFA) led to distinct 3D‐QSAR models for propafenone and phenothiazine analogs. Recently, several pharmacophore models have been generated for diverse sets of ligands. Starting from a training set of 15 propafenone‐type MDR‐modulators, we established a chemical function‐based pharmacophore model. The pharmacophoric features identified by this model were (i) one hydrogen bond acceptor, (ii) one hydrophobic area, (iii) two aromatic hydrophobic areas, and (iv) one positive ionizable group. In silico screening of the Derwent World Drug Index using the model led to identification of 28 compounds. Substances retrieved by database screening are diverse in structure and include dihydropyridines, chloroquine analogs, phenothiazines, and terfenadine. On the basis of its general applicability, the presented 3DQSAR model allows in silico screening of virtual compound libraries to identify new potential lead compounds.

01 Nov 2000·Journal of Medicinal ChemistryQ1 · MEDICINE

Classification of Multidrug-Resistance Reversal Agents Using Structure-Based Descriptors and Linear Discriminant Analysis

Q1 · MEDICINE

Article

Author: Bakken, Gregory A. ; Jurs, Peter C.

Linear discriminant analysis is used to generate models to classify multidrug-resistance reversal agents based on activity. Models are generated and evaluated using multidrug-resistance reversal activity values for 609 compounds measured using adriamycin-resistant P388 murine leukemia cells. Structure-based descriptors numerically encode molecular features which are used in model formation. Two types of models are generated: one type to classify compounds as inactive, moderately active, and active (three-class problem) and one type to classify compounds as inactive or active without considering the moderately active class (two-class problem). Two activity distributions are considered, where the separation between inactive and active compounds is different. When the separation between inactive and active classes is small, a model based on nine topological descriptors is developed that produces a classification rate of 83.1% correct for an external prediction set. Larger separation between active and inactive classes raises the prediction set classification rate to 92.0% correct using a model with six topological descriptors. Models are further validated through Monte Carlo experiments in which models are generated after class labels have been scrambled. The classification rates achieved demonstrate that the models developed could serve as a screening mechanism to identify potentially useful MDRR agents from large libraries of compounds.

01 Jan 1992·Cancer Chemotherapy and PharmacologyQ4 · MEDICINE

Reversal of multidrug resistance by phenothiazines and structurally related compounds

Q4 · MEDICINE

Article

Author: Avner Ramu ; Nili Ramu

The multidrug-resistance (MDR)-reversal activity of 232 phenothiazines and structurally related compounds was tested in MDR P388 cells. Such activity was found among compounds exhibiting two ring structures (phenyl, cyclopentyl, cyclohexyl, thienyl or 5-norbornen-2-yl but not pyridinyl) linked by a variety of bridge types and possessing a secondary or tertiary amine group. Among 192 such compounds, 31.8% displayed good activity (MDR-reversal ratio, greater than or equal to 10) and 8.3%, outstanding activity (MDR-reversal ratio, greater than or equal to 30). In a subgroup comprising 56 compounds with a carbonyl residue, 4 with sulfuryl residue and 1 with thienyl residue, 42.7% showed good activity and 18%, outstanding activity. The contribution of these residues to the MDR-reversal activity was particularly evident among compounds containing a cyclic tertiary amine. Among 49 such compounds, 51% displayed good activity and 20.4%, outstanding activity, whereas among the 85 compounds lacking such groups, only 31.8% showed good activity and 4.7%, outstanding activity. Enhancement of this activity by the carbonyl group is also obtained when the latter is part of an amide bond of a tertiary amine. As compounds with a carbonyl group located on the rings, on the bridge to the amine group or beyond the amine are efficient MDR reversers, it seems that the exact molecular location of the carbonyl group is not critical for the elicitation of this activity.

100 Deals associated with AHR-16303B

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Indication	Highest Phase	Country/Location	Organization	Date
Hypertension	Preclinical	-	Pfizer Inc.	-
Hypertension	Preclinical	United States	AH Robins LLC	-
Myocardial Ischemia	Preclinical	-	Pfizer Inc.	-
Myocardial Ischemia	Preclinical	United States	AH Robins LLC	-
Thrombosis	Preclinical	-	Pfizer Inc.	-
Thrombosis	Preclinical	United States	AH Robins LLC	-

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