Enamine holds expertise in organofluorine chemistry with over 50 scientific papers in this research area published in the last 10 years. Our chemists are heavily involved in research on new synthetic methodologies for introducing fluorine atoms into a wide range of aliphatic/aromatic heterocyclic cores and various side chains.

The fragment selection has been made with emphasis on high structural quality of molecules and easy performance and interpretation of ¹⁹F NMR screening results. Very simple/trivial cores with overused chemistry; compounds having more than two stereocenters, showing rotamers, diastereoisomeric mixtures, as well as molecules prone to aggregation have been removed from the set.

Key features

• Experimentally confirmed solubility in PBS buffer at 1 mM, in DMSO at 200 mM
• ¹⁹F NMR chemical shifts are provided for all compounds in aqueous PBS or DMSO solutions.
• Full Ro3 compliance, no reactive and unstable compounds, stability in DMSO solution has been tested.
• 15 200 in-stock analogues are available (MW 160…400)
• Cherry-picking is possible; delivery in any custom format including dry powders or DMSO solution in vials, microtubes or plates within 1–3 weeks

Examples of the molecules in the library

Single-fluorine Fragments

Z1255430272

Z2096088803

Z1162448372

Difluoromethyl-substituted Fragments

Z1446855494

Z2092370865

Z2048189929

Trifluoromethyl-substituted Fragments

Z1258578396

Z1415893855

Z235344875

G protein coupled-receptors (GPCRs) are to date the most successful family of druggable targets in modern Drug Discovery. More than 1/3 of all approved drugs target GPCRs.

We have carefully selected 53 440 diverse compounds specifically targeting GPCR's. All compounds are stored as dry materials and they can be acquired in diverse custom formats. Alternatively, we can promptly supply a copy of the pre-plated GPCR Library having 53 440 compounds, that can be also made in a customized ready-to-screen formats. Using our GPCR Library for hit discovery you receive multiple benefits allowing you to save on time and costs in lead generation:

• Dry stock of over 4.6M compounds for hit resupply and hit expansion
• Low-cost synthesis of analogues within only 3 weeks through our REAL Database technology
• Medicinal chemistry support enhanced with on-site broad ADME/T panel

You have also an option to screen the library directly at Enamine. In this case we will be happy to offer you discount on library cost depending on the collaboration scope.

Library design

We used combination of different in silico approaches to design our GPCR Library. The library covers a wide range of GPCR-targets and possesses most important features for initial Drug Discovery – Novelty and High Diversity. A combined approach, including framework 2D-fingerprint similarity search, careful selection of GPCR-privileged scaffolds and common structural motifs with extension by 3D pharmacophore searches, was used to search of potential actives. MedChem refinements were applied to the combined pool of compounds, resulting in a unique set of 53 440 high quality small molecules.

All compounds from Enamine's GPCR Library possess high chemical novelty and drug-like molecular properties with attractive structures.

The following molecular parameters were applied in construction of the library:
MW = 200...550, ClogP = -1.5...5.5, TPSA ≤ 150 Å², RotBonds ≤ 9, HBD/HBA ≤ 4/10.

Examples of the molecules

Examples of compounds from GPCR Library having pharmacophore similarity to Ambrisentan and bearing scaffolds that are bioisosteric to the spiro-piperidine-indane privileged fragment

Novel sp³-enriched scaffolds specifically designed as cores for Enamine's GPCR Library

Enamine's GPCR Library includes two sub-libraries focusing on allosteric modulators and lipid GPCRs.

Library design

Overcoming the difficulty of delivering therapeutic agents to the specific CNS sites is one of the major challenges in discovery of new treatments of neurological disorders. The criteria for selection of CNS-active molecules which are able to penetrate blood-brain barrier (BBB) were low polar surface area (TPSA < 70 Å² (median value 48 Å²), cf. 45 Å² for the marketed CNS drugs), low degree of possible hydrogen bond formation (total number of hydrogen bond acceptors and donors are less than 8) and low ClogP values (average is 1.63). Further selection was driven by evaluation of CNS MPO desirability scores for each candidate compound.

The parameters for selection included:
CNS MPO ≥ 4 (ClogP, ClogD, MW, TPSA, HBD, and pKa for most basic center)
MW ≤ 350 (median value 283, cf. 305 for the marketed CNS drugs),
ClogP ≤ 3.0 (mean value 1.63, cf. 2.8 for the marketed CNS drugs),
Amide groups ≤ 1, HBD ≤ 2, QProp CNS value > 0.

Key features

Modern CNS drug discovery notions suggest that conformational constraints and rigidity of the molecules are important structural features of CNS-active compounds. Our selection of CNS compounds was enriched with recently synthesized molecules having sp³-rich saturated ring cores of various architectures including spirocyclic (1 341 compounds, 14.5%), bridged and fused scaffolds (4 106 compounds, 44.5%).

Novelty

Compounds included into CNS focused Library were selected from all three screening collections - HTS, Advanced and Premium. Preference was given to the compounds synthesized within the last 4 years, based on innovative scaffolds and with use of advanced building blocks to enhance the novelty value of the library.