Scaffold Hopping with Molecular Field Points:  Identification of a Cholecystokinin-2 (CCK₂) Receptor Pharmacophore and Its Use in the Design of a Prototypical Series of Pyrrole- and Imidazole-Based CCK₂ Antagonists

Abstract

A new molecular modeling approach has been used to derive a pharmacophore of the potent and selective cholecystokinin-2 (CCK(2)) receptor antagonist 5 (JB93182), based on features shared with two related series. The technique uses "field points" as simple and effective descriptions of the electrostatic and van der Waals maxima and minima surrounding a molecule equipped with XED (extended electron distribution) charges. Problems associated with the high levels of biliary elimination of 5 in vivo required us to design a compound with significantly lower molecular weight without sacrificing its nanomolar levels of in vitro activity. Two new series of compounds were designed to mimic the arrangement of field points present in the pharmacophore rather than its structural elements. In a formal sense, two of the three amides in 5 were replaced with either a simple pyrrole or imidazole, while some features thought to be essential for the high levels of in vitro activity of the parent compounds were retained and others deleted. These compounds maintained activity and selectivity for this receptor over CCK(1). In addition, the reduction in molecular weight coupled with lower polarities greatly reduced levels of biliary elimination associated with 5. This makes them good lead compounds for development of drug candidates whose structures are not obviously related to those of the parents and represents the first example of scaffold hopping using molecular field points.

Rationalizing the Activities of Diverse Cholecystokinin 2 Receptor Antagonists Using Molecular Field Points

“…We have not yet developed software that is specifically directed toward the lead optimization process. Nevertheless, we have already shown that it is possible to scaffold hop from one chemotype to another using a basic understanding of the origins of particular field point patterns 12 and plan to investigate this aspect further.…”

3D QSAR studies of 1,3,4-benzotriazepine derivatives as CCK2 receptor antagonists

“…Sinha et al [34] have performed traditional QSAR studies on a series of 1,4-benzodiazepine CCK 1 R and CCK 2 R antagonists and determined logP and an indicator variables to contribute to the antagonistic activity. Recently a new molecular modeling approach based on field points as a simple descriptor of electrostatic and van der Waals maxima and minima surrounding a structurally diverse series of nonpeptidic analogues of JB 93182 has been used to derive a pharmacophore model for CCK 2 R antagonists [35]. Tairi-Kellou et al [36] have described traditional QSAR equations correlating electronic properties of 1,4-benzodiazepines to CCK 1 R and CCK 2 R antagonism.…”

Fuzzy Tricentric Pharmacophore Fingerprints. 1. Topological Fuzzy Pharmacophore Triplets and Adapted Molecular Similarity Scoring Schemes

“…Relationships between activity and pharmacophore feature distribution descriptors have been intensely studied in chemoinformatics, either in terms of (a) QSAR model buildup or (b) binding pharmacophore [6][7][8] elucidation attempts. There is however no fundamental distinction between (a) and (b)sselecting and weighing specific elements of the vector describing the overall pharmacophore pattern of a molecule, as in (a), may in principle allow the backtracking of the important, activityenhancing variables to the actual pharmacophore features in the molecules and thus translate a QSAR model into a pharmacophore hypothesis in the sense of (b).…”