title: 3D-QSAR analysis of TRPV1 inhibitors reveals a pharmacophore applicable to diverse scaffolds and clinical candidates.
abstract: 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; R(2)=0.9 and Q(2)=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.
authors.affiliation: Department of Computational Chemistry, Jubilant Biosys Limited, #96, Industrial Suburb, 2nd Stage, Yeshwanthpur, Bangalore 560 064, India; Shanmugha Arts, Science, Technology, and Research Academy, Thanjavur 613 402, Tamil Nadu, India.
authors.forename: Rajendra
authors.initials: R
authors.lastname: Kristam
authors.forename: Vinod
authors.initials: V
authors.lastname: Parmar
authors.forename: Vellarkad N
authors.initials: VN
authors.lastname: Viswanadhan
mesh_terms: D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D007477:Ions / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D010879:Piperazines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D015203:Reproducibility of Results; D055672:Static Electricity; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism
chemical_list: D007477:Ions; D010879:Piperazines; D050916:TRPV Cation Channels; C494484:TRPV1 receptor
keywords: 3D-QSAR analysis of TRPV1 inhibitors; Phase QSAR modeling; Piperazinyl-aryl series; TRPV1 inhibitors; TRPV1 pharmacophore