6-Substituted Benzopyrans as Potassium Channel Activators:  Synthesis, Vasodilator Properties, and Multivariate Analysis

Abstract

During the last 10 years compounds have been discovered which can activate or block KATP channels. In particular, K channel activators (KCA) have been found to be smooth muscle relaxants with their main utility in hypertension and bronchodilation. In this paper we describe the synthesis of new KCA of the benzopyran type with a fixed 4-substituent and a systematic variation in the 6-position. The relaxant potency in rat aorta and trachea was used for biological characterization of the benzopyrans. In both biological test systems, they exhibit potency ranges of more than 3 log units. Structure-activity relationships are investigated by principal component analysis (PCA) and partial least-squares (PLS) analysis. Most striking outliers in an initial PLS analysis of the entire database were the unsubstituted 6-H compound 13 as well as 34 and 35. For the remaining set of 31 compounds, a 3-component PLS model explains the variance in biological activity to 81% in the aortic and to 82% in the tracheal test system. 6-Substituents influence affinity by a direct (presumably dipolar) interaction with the receptor site. According to the 2D-plot of the partial PLS weights, a strong electronegativity as well as high values for the integy moment and for the heat of formation in water dominate the first component; low values for substituent size (as defined by globularity or surface) are in addition favorable for high potency. High lipophilicity and low minimum energies of interaction dominate the second component. Chemical descriptors for the biological potency of the test set in rat aorta and rat trachea are very similar according to the almost identical projection of the Y-variables onto the X-component space.

Structure-Activity Relationships of KATP Channel Openers

“…The relaxant potencies of 6-substituted benzopyrans in rat aorta and trachea were subjected to detailed SAR studies via partial least squares (PLS) analysis [31,32]. A strong electronegativity, high values for the integy moment and the heat of formation in water as well as low values for substituent size favor high dilator potency.…”

A Novel Roscovitine Derivative Potently Induces G1-Phase Arrest in Platelet-Derived Growth Factor-BB-Activated Vascular Smooth Muscle Cells

“…For substrates and kinases used, see Supplemental In Silico Prediction of the Pharmacokinetic Profile of LGR1406 Compared with ROSC. VolSurf is an established computational procedure to produce 2D molecular descriptors from 3D molecular interaction energy grid maps that is used during drug design, pharmacokinetics profiling, and screening (Mannhold et al, 1999;Cruciani et al, 2000;Cianchetta et al, 2004;Crivori et al, 2004;Berellini et al, 2005). For the comparison of the pharmacokinetic profiles of LGR1406 and ROSC, we used the protein binding, volume distribution (VD), and CYP3A4 metabolic stability model.…”

Global physicochemical properties as activity discriminants for the mGluR1 subtype of metabotropic glutamate receptors

“…Globularity has been defined in the past to describe the shape of polypeptides, but it has been extended to characterize the overall shape of molecules. 43 The parameter G is defined as the ratio of the area of a sphere (A sp ) with a volume (V) equivalent to the molecular volume (V mol ) over the area of the actual molecular surface (A):…”