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Ion Channel Libraries

Download General Ion Channel Library SDF
Download Nav1.7 Targeted Library SDF
Download Calcium Channel Targeted Library SDF

Ion channels are among the most important therapeutic targets in developing of new highly effective medical treatments in the same time being one of the most difficult tasks in Medicinal Chemistry. Ion channels are critical for cell-to-cell communication and regulate multiple biological processes dysfunction of which may lead to widespread diseases and pathologic conditions such as diabetes, neuropathic pain, cardiovascular diseases, cerebral and peripheral vascular disorders, asthma, neurodegenerative and other disorders.

General Ion Channel Library

22 000 compounds

We applied multipronged approach in rational library design to gain a qualitative set of molecules focused on ion channel targets. A major contribution was made in the lead-oriented synthesis program at Enamine focused on increasing of novelty and structural diversity. The project has already yielded over 17 000 lead-like compounds built on novel scaffolds featuring saturated rings that have been recognized as potential ion channel blockers.

Pharmacophore ligand-based biased analyses were run on reference set of active ligands (≤10 nM) resulting in three main pharmacophore motifs frequently occurring in reported ligands. Obtained models were imposed into HTS & Advanced Collections and applied to the REAL lead-like database. One of the common features of derived pharmacophores was presence of tertiary/secondary amino group.

Additional compounds were added to the library after analysis of privileged motives of known ion channel blockers and after morphing of some recently discovered ion channel and TRPV1 modulators. General Medicinal Chemistry overview finalized the library profile: molecular parameters, solubility requirements and general pharmacokinetic obstructions.

Parameter Range
MW 180 … 400
ClogP -3.5 … 3
AlogS ≥ 30 μg/mL
Fsp3 ≥ 0.35
Hb Donors 0 … 3
Hb Acceptors 0 … 7
TPSA 30 … 100 Å2
Strict MedChem filters and rules have been applied 

Examples of compounds from the Library in relation to approved drugs targeted Ion Channels

general-ion-channel-library-scheme.png

Molecular properties of the Library

ion-channel-library-mw.png ion-channel-library-clogp.png
ion-channel-library-fsp3.png ion-channel-library-tpsa.png

 

Nav1.7 Targeted Library

3 900 compounds

Nav1.7 voltage-gated ion-channel is considered to be an important component in nociception. Therefore selective Nav1.7 channel blockers are considered as potential novel analgesics. Analyzing the structures of recently developed ligands several main features of library design has been identified:

  • Flat aromatic cores are the most abundant in known ligands.
  • Highly polar backbone fragments/moieties are presented by 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 6 200 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.

Examples of compounds from the Library in relation to approved drugs targeting ion channels

nav1-7-targeted-library-examples.png

Molecular properties of the Library

nav1-7-targeted-library-mw.png nav1-7-targeted-library-logp.png
nav1-7-targeted-library-fsp3.png nav1-7-targeted-library-tpsa.png

 

Calcium Channel Targeted Library

4 500 compounds

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.

Library design

  • Privileged chemotypes such as dihydropyridines, GABA-analogues, succinimides, 4-substituted prolines, and quinazolines were included in the library.
  • Scaffold hopping yielded a rich variety of compounds built on unique analogues of piperazine, 4-aminopiperidine, and other cores, chosen as a bioisosteric replacement of diamine structure of known calcium channel blockers.
  • Pharmacophore modelling was carried out for several relevant calcium channel blockers resulting in about 1 700 compound set.

Key features

  • Both known chemotypes and novel scaffolds identified in our in silico studies and MedChem based scaffold hopping projects were included in Enamine voltage-gated library;
  • Average Fsp3 0.38, average TPSA 60.5 Å2;
  • 100% Ro5 appliance and 86% lead-likeness.
Parameter Range
Hb Donors 0 … 4
Hb Acceptors 1 … 8
RotBonds 0 … 10
TPSA 3 … 140 Å2

Examples of compounds from Calcium Channel Targeted Library

chemotypes scaffolds
pharmacophores


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