3D-QSAR analysis of TRPV1 inhibitors reveals a pharmacophore applicable to diverse scaffolds and clinical candidates

•Development of a pharmacophore model for TRPV1 antagonists is explained.•A 3D-QSAR model is built based on a dataset of piperazinyl-aryl compounds and validated, using PHASE.•The QSAR model is able to explain all the experimental SAR trends observed.•The pharmacophore model is found to be applicable to most of the TRPV1 clinical candidates.•The pharmacophore model can be used to find new chemotypes for modality-specific TRPV1 antagonists.

TRPV1 (Transient Receptor Potential Vanilloid Type 1) receptor, a member of Transient Receptor Potential Vanilloid subfamily of ion channels, occurs in the peripheral and central nervous system, and plays a key role in transmission of pain. Consequently, this has been the target for discovery of several pain relieving agents which have undergone clinical trials. Though several TRPV1 antagonists have progressed to become clinical candidates, many are known to cause temperature elevation in humans, halting their further advancement, and signifying the need for new chemotypes. Different chemical classes of TRPV1 antagonists share three important features: an amide or an isostere flanked by an aromatic (or fused aromatic) ring with polar substitutions on one side, and a hydrophobic group on the other. Recent work identified new series of compounds with these and additional features, leading to improvement of properties, and development of clinical candidates. Herein, we describe a 3D-QSAR model (n = 62; R2 = 0.9 and Q2 = 0.75) developed from the piperazinyl-aryl series of compounds and a novel 5-point pharmacophore model is shown to fit several diverse scaffolds, six clinical candidates, five pre-clinical candidates and three lead compounds. The pharmacophore model can aid in finding new chemotypes as starting points that can be developed further.

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