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CNS-Targeted Library

47 000 compounds

To enable the discovery of new CNS actives we employed versatile approaches, bearing in mind molecular properties preferable for BBB permeability. The resulting final selection of 47 000 compounds from the initial 2 Million+ screening collection possess the most preferable CNS-targeted properties and structural features, maintaining high level of novelty and diversity.

Library design

Overcoming the difficulty of delivering therapeutic agents to specific CNS sites is one of a major challenge for treatment of the majority of CNS 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, the everage is 1.63. Further selection was driven by evaluation of CNS MPO desirability scores for each candidate compound. The algorithm included parameters for selection included:

Parameter Range Parameter  
MW 170 ... 350 RotBonds ≤ 4
ClogP -0.5 ... 3.0 Aromatic rings 1 ... 3
Hb Donors ≤ 2 Fsp3 0.15 ... 0.8
TPSA ≤ 70 Å2 QPPCaco-2 > 500
Amide groups ≤ 1 Basic N ≤ 2
Total H-bonding < 8 QPlogBB -1.0-0.8
Carboxylic acids ≤ 1 CNS > 0
CNS MPO ≥ 4 pKa_bs -1.5 ... 8.0

Structural 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%).

Z1823993569 Z2087745281 Z2188171678 Z397719902

Z1823993569

Z2087745281 Z2188171678 Z397719902

Novelty

Compounds included into CNS focused Library were selected from all three collections - HTS, Advanced and Premium. Preference was given to the compounds synthesized within the last 5 years, based on innovative scaffolds and with use of advanced building blocks to enhance the novelty value of the library.

Diversity

Structures of Enamine CNS-target library were analyzed using similarity scoring to identify the most diverse compounds.

Absence of toxic and reactive motifs

Toxicity and PAINS filters were applied to remove all high reactive and toxic motifs.

Purity

All compounds are more than 90% pure as confirmed by LCMS and/or 1H NMR data.

Availability, follow-up and further scale-up

All compounds were synthesized at Enamine and are available on stock in over 10 mg quantities and scale-up is guaranteed. Further rapid and non-expensive lead generation and optimization can be performed at Enamine.

Molecular properties of CNS-Targeted Library

molecular wieght clogp
tpsa fsp3
RB HBD

Other properties include: mean RotBonds 3.36, mean ring count 3.1, mean (N + O) count 3, and mean Fsp3 0.4.

List of references
  1. Pajouhesh, H., Lenz, G. R. NeuroRX 2005, 541.
  2. Hitchcock Curr. Opin. Chem. Biol. 2008, 318.
  3. Pardridge W. M. J. Cer. Blood Flow Metabol. 2012, 32, 1959.


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