New! – Macrocycle CNS Library


Subset with potential application to CNS drug discovery

Introduction

Topologically, macrocycles have the unique ability to span large surface areas while remaining conformationally restricted compared to acyclic molecules of equivalent molecular weight. Macrocyclization also reduces overall polarity and enhances membrane penetration compared to acyclic molecules of equivalent molecular weight. Taken together these attributes make macrocycles a powerful approach for any lead discovery program against challenging targets. However, for CNS drug discovery, macrocyclic leads are not typically thought of as attractive starting points as the TPSA and HBD count tends to be outside of what is considered an acceptable range for blood brain barrier penetration. By determining the number of internal hydrogen bonds a macrocyclic molecule makes in a solvent with a low dielectric constant and discounting the HBD count and TPSA (-20 Å per HBD) ChemBridge has identified a subset of more than 4,000 macrocyclic compounds from its Macrocycle Library predicted to have a high probability of good blood brain barrier penetration based on an MPO scoring approach.

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CNS Multiparameter Optimization (MPO) score

A fundamental challenge for the design of CNS penetrant drugs is the need to cross the BBB. An important observation for BBB permeable compounds is their physicochemical parameters 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 first described by Verhoest and Wager et al in 2009 and more fully described in a 2010 article1 known as the CNS Multiparameter Optimization (MPO) score. 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 score is between 0-6 with scores ≥ 4.0 widely used as a cut-off to select compounds for hit finding in CNS therapeutic area drug discovery programs

A key factor in calculating the CNS MPO score for macrocycles was to predict the possibility of the formation of intramolecular hydrogen bonds when the macrocycles is passing through the membrane and to adjust the calculated properties accordingly.

Methodology

A detailed 3D conformational analysis of macrocycles from the ChemBridge Macrocycle Library (approximately 6,600 synthetic macrocycles) was performed to examine the number of intramolecular hydrogen bonds. Data from the conformational analysis was used to adjust the HBD and tPSA values and resulting MPO score for each compound and identified a subset with an “adjusted MPO” score ≥ 4.0.

    The following process was applied to all macrocyclic compounds from the ChemBridge macrocyclic screening library
  1. Remove macrocycles with carboxylic acids3 (n=210).
  2. Retain all macrocycles with CNS MPO ≥ 4.0 (n=1,269; these meet the MPO cutoff without need to form intramolecular hydrogen bonds)
  3. Remove all macrocycles with CNS MPO < 4.0 and without ability to achieve adjusted CNS MPO ≥ 4.0 with all HBD internally hydrated
  4. For remaining macrocycles with CNS MPO < 4.0 but with potential to form internal hydrogen bonds and achieve an adjusted CNS MPO ≥ 4.0, perform an extensive conformational search with molecular mechanics minimization, fast implicit vibrational analysis and short molecular dynamics simulation4
  5. Count maximum number of intramolecular hydrogen bonds predicted from conformational search (conformations analyzed were within 2.8 kcal/mol of minimum)
  6. Calculate the adjusted MPO score taking into account the predicted intramolecular hydrogen bonds; retain macrocycles with adjusted CNS MPO of ≥ 4.0 (n=3,129)
  7. Combine macrocycles from step 2 and 6 as CNS Subset (n=4,398)

The compound shown in Figure 1 has a CNS MPO score of 3.0 when calculated using standard CNS MPO methodology (without accounting for potential to form internal hydrogen bonds). After applying the process outlined above, the adjusted CNS MPO score is 4.6 based on the ability of the macrocycles to form 3 internal hydrogen bonds therefore qualifying the compound for the Macrocycle CNS Subset.


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for background on the ChemBridge macrocycles.


For more details on the ChemBridge Macrocycle CNS Subset please contact sales@chembridge.com

References

  1. Wager TT, Hou X, Verhoest PR; Villalobos A. 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 Jun 16; 1(6): 435–449. PMID 22778837 (put a link behind the PMID number and launch a new window and link to https://www.ncbi.nlm.nih.gov/pubmed/22778837)
  2. Hickey JL, Zaretsky S, St Denis MA, Kumar Chakka S, Morshed MM, Scully CC, Roughton AL, Yudin AK. Passive Membrane Permeability of Macrocycles Can Be Controlled by Exocyclic Amide Bonds, J. Med. Chem. 2016, 59(11), 5368−5376 PMID 27120576 (put a link behind the PMID number and launch a new window and link to https://www.ncbi.nlm.nih.gov/pubmed/27120576)
  3. Ghose AK, Herbertz T, Hudkins RL, Dorsey BD, Mallamo JP. Knowledge-Based, Central Nervous System (CNS) Lead Selection and Lead Optimization for CNS Drug Discovery. ACS Chem. Neurosci. 2012, 3(1), 50−68 PMID 22267984 (put a link behind the PMID number and launch a new window and link to https://www.ncbi.nlm.nih.gov/pubmed/ 22267984)
  4. Labute P, Williams C, Feher M, Sourial E, Schmidt JM. Flexible Alignment of Small Molecules. J. Med. Chem., 2001, 44(10), 1483–1490 PMID 11334559 (put a link behind the PMID number and launch a new window and link to https://www.ncbi.nlm.nih.gov/pubmed/ 11334559)

Related Products: CNS-Set, CNS-MPO


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