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 4.7M+ 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.

Modern drug discovery requires contemporary compound libraries. We synthesize 300,000 new compounds annually and select the best candidates for our compound libraries. We offer over 100 fast-to-deliver pre-plated compound libraries for various research needs, from large-scale HTS screens to assay-specific and proteomics studies.

• Positive screening outcome. We conduct in-depth analysis of the research field and collaborate with leading industry experts to design our libraries.
• Premium quality. We produce compound libraries using only over 90%-pure compounds with analytics (LCMS and/or NMR) not older than one year. We filter compounds that are unstable in DMSO, have poor solubility, and undesirable salts. We also track the number of freeze-thaw cycles to determine pre-plated libraries shelf life based on their nature (cf. covalent vs non-covalent and other sensitive classes). When resupplying the hits, we follow our defined procedure, tracking the compound batches and their analytics. We purify or even resynthesize samples free of charge if they are of poor quality.
• Resupply from dry powders. For the library preparation, we use compounds available at 10+ mg in our stock so that they can be resupplied from the same batch. We have a program in place to maintain the dry sample stock levels through resynthesis for compounds present in REAL Space. For the best and fastest results, we encourage integrated lead discovery projects involving our biological screening, computational chemistry, efficient Hit-to-Lead using our REAL Space, ADMET/PK, and MedChem support.