Sodium voltage-gated ion channel considered to be an important component in nociception. Therefore, selective Nav1.7 channel blockers are considered as important novel analgesics.

Analyzing the structures of recently developed ligands several main features have been identified:

• the most abundant are relatively flat aromatic cores;
• presence of highly polar backbone fragments/moieties (e.g. CONH₂, SO₂NHR, polar heterocycles, etc);
• compounds lay squarely in the middle of drug-like chemical space.

A set of substructure queries and 2D-fingerprintes based on found common structural motives and pharmacophores was used in searching Enamine screening collection to result in 5 440 compounds after application of medchem filters. The Nav1.7 Targeted Library is rich in compounds bearing saturated backbones that can be often seen in structures of other ion-channel blockers. All compounds meet requirements of Ro5, and 67% compounds are considered lead-like.

Calcium ion channels are responsible for an unusually large variety of physiological functions. Calcium ions entering the cell through voltage-gated channels serve as the second messenger of electrical signaling, initiating many different cellular events. As a target class calcium channels offer both challenges first of in designing selective antagonists of the channel subtypes and great opportunities following proof-of-concept provided by the marketed drugs.

Enamine voltage-gated targeted library encompasses both known chemotypes and molecules based on novel scaffolds identified in our in silico studies and MedChem based scaffold hopping projects.

Main futures of the library:

• Lead-likeness: 86%
• Average Fsp3 0.38; average TPSA 60.5 Ų
• Novel Chemotypes

Library design

We have undertaken in-depth analysis of known calcium channel blockers and carefully selected 10 560 most promising drug-like structures from our screening collection exceeding 4.4M+ small molecular weight compounds.

Privileged chemotypes such as dihydropyridines, GABA-analogues, succinimides, 4-substituted prolines, and quinazolines were included in the library.

Pharmacophore modeling was carried out for several relevant calcium channel blockers resulting in about 1 700 compound set.

Scaffold hopping Structures of numerous known calcium channel blockers contain piperazine or 4-aminopiperidine. Recently several successful examples of bioisosteric replacement of these motifs by other diamine cores have been reported. We have extended this approach to a rich variety of compounds built on unique analogues of piperazine and 4-aminopiperidine available exclusively from Enamine and continued with other cores, e.g. imidazopiredazines, providing novel sets of compounds.

Molecular properties Drug like compounds with the most attractive structural and physical chemical properties. HBond Donors 0… 4, HBond Acceptors: 1 … 8, Rotatable Bonds: 0 ... 10, TPSA 3 … 140 Ų

Support

• Hit Confirmation: QC check, HPLC repurification, resynthesis
• Hit follow-up: analogs search from stock or REAL Database
• Fast hit exploration libraries synthesis

We offer comprehensive support in developing your hit compounds. Naturally such programs are realised most efficiently when biological actives originate from our screening collection. However, even if the hit compounds are from the collections of other vendors lead identification and optimization projects can proceed most productively in our hands. Sometimes for this we only need to synthesize first examples of the given chemical series and validate synthesis route.