New! – CNS-MPO Library


CNS MPO scored screening compounds for CNS drug discovery

Highlights

  • High quality leadlike, small molecule compounds suitable for CNS focused research programs
  • High probability of blood-brain barrier (BBB) penetration with improved clearance and safety profile
  • Structurally diverse subsets available with options to bias towards hit-finding and leadlike subsets
  • Custom select from more than 250,000 structures to meet your specific requirements
  • Additional structural analogs for SAR studies represented within the CNS-MPO Library

Introduction

ChemBridge has created a new CNS-focused compound selection, the CNS-MPO Library, to support CNS drug discovery programs. Hits from the libraries are predicted, based on a multiparameter optimization (MPO) approach, to have a higher probability of crossing the BBB. The CNS-MPO Library represents a subset of compounds from ChemBridge’s stock of more than 1.1 million leadlike and druglike small molecule screening compounds representing a wide range of different chemotypes.


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to download a copy of the CNS-MPO product sheet.


CNS Multiparameter Optimization (MPO) Score

A fundamental challenge for the design of CNS penetrant drugs is the need to cross the BBB. Physiochemical parameters for BBB permeable compounds form a smaller subset within the property space of oral drugs. To best define the physicochemical properties for CNS library design ChemBridge selected a weighted scoring approach described by Wager et al.1,2 The CNS MPO score is now a well-recognized algorithm in the CNS focused medicinal chemistry community. The algorithm uses a weighted scoring function assessing 6 key physicochemical properties (cLogP, cLogD, MW, tPSA, HBD, and pKa) for BBB penetration, CYP mediated metabolism and inhibition of dofetilide binding. The CNS MPO score is between 0 to 6.0 with scores ≥ 4.0 widely used as a cut-off to select compounds for hit finding in CNS therapeutic area drug discovery programs. Assessment of 616 compounds from Lilly’s database with measured unbound concentrations in the brain (Cu,b) confirmed increasing MPO score correlates with increased Cu,b.3


Selection

The following approach was used to select compounds for inclusion in the CNS-MPO Library:
  • Filter to remove compounds with undesirable structural features
  • Remove compounds with carboxylic acid groups due to low probability of BBB permeability
  • MW range of 250 to 450 inclusive to allow for creation of hit-finding or lead-like biased selections
  • CNS MPO score ≥ 4.0
  • Remove compounds with tPSA ≥ 100Å to eliminate high MPO score compounds with undesirable tPSA
  • Limit cLogD range to 0 to 5.0 (inclusive) to eliminate high MPO score compounds with extreme cLogD values

The CNS-MPO Library can be further refined by using structural diversity analysis, by focusing on a hit-finding subset (MW range 300 to 450), or by focusing on a lead-like subset (MW range 250 to 400; tPSA high end boundary of 90 Å or less; option to re-score using CNS Lead MPO5)


Format

  • Download structures and custom select CNS-MPO Library compounds
  • Compounds can be provided in 96-well or 384-well format
  • Compounds are available dry or as DMSO solutions

References

  1. Wager TT et al. Moving beyond rules: The development of a central nervous system multiparameter optimization (CNS MPO) approach to enable alignment of druglike properties. ACS Chem. Neurosci. 2010, 1, 435-449.
  2. Wager, TT et al. Central nervous system multiparameter optimization desirability: Application in drug discovery. ACS Chem. Neurosci. 2016, 7, 767-7
  3. Rankovic, Z. CNS drug design: balancing physicochemical properties for optimal brain exposure. J. Med. Chem., 2015, 58 (6), 2584–2608
  4. Ghose AK et al. Knowledge-based, central nervous system (CNS) lead selection and lead optimization for CNS drug discovery. ACS Chem. Neurosci. 2012, 3, 50−68.
  5. Mayol-Llinàs J et al. Assessing molecular scaffolds for CNS drug discovery. Drug Discov. Today. 2017, 7, 965-969.

Related Products: CNS-Set, Macrocycle CNS


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