Fragments

Fragments

3D-rich Fragment Libraries

Library Design

LCC have designed a 3D-rich fragment library based on nine sp3-rich heterocyclic cores:

Liverpool ChirChem 3D Rich Fragments

The library consists of 43,226 unique compounds that are chemically tractable using LCC’s synthetic methods.

Library Properties

Histograms of LCC Compounds
LCC Fragments Graph

MW
Solubility (mM)
AlogP
#H Bond Donors
#H Bond Acceptors
Average
234.43
148.19
1.03
0.99
3.12
SD
50.7
431.0
1.5
0.8
3.0

Rule of 3 library

Library Design

  • Sublibrary of Building block/scaffold library
  • No protecting groups
  • No esters
  • Acceptable aqueous solubility
  • Rule of 3 compliant
  • No PAINS, Rishton fragments, “Bad groups” etc.

    Baell, J. et al. J Med Chem, 2010, 53(7), 2719
    Rishton, G. M. DDT, 1997, 2(9), 382
    Hann, M. J. Chem. Inf. Comput. Sci., 1999, 5, 897
    Muegge, I. Med. Res. Rev., 2003, 23(3), 302

Final set of criteria:

  • Calculated aqueous solubility > 1 milliM
  • AlogP ≤ 3
  • Molecular weight ≤ 300
  • #H bond donors ≤ 3
  • #H bond acceptors ≤ 3
  • PSA ≤ 60 Å2
  • #Rotable bonds ≤ 3
Histograms of LCC Compounds
LCC Fragments Graph

MW
Solubility (mM)
AlogP
#H Bond Donors
#H Bond Acceptors
Average
192.18 144.08
0.94
0.83 2.52
SD
33.2
380.0
1.0 0.7 0.6

CNS Library

LCC’s synthetic technologies allow the production of novel, heterocyclic based small molecules. Our patented technology provides access to chiral piperidines.Upon analysis of the FDA approved drugs, we noticed that piperidines are the most frequently occurring heterocycle. In addition, piperidines are also the most prevalent heterocycle in clinically approved CNS (Central Nervous System) compounds.

Therefore, we set out to apply our technology to the synthesis of a focussed library targeted at the CNS.

Examination of the physicochemical/Lipinski space of LCC compounds cf CNS approved drugs there is a high degree of similarity, i.e. low MW (<400), low logP (<5), #H bond donors (95% library <5), #H bond acceptors (<8)

Histograms of LCC Compounds
Histograms of LCC Compounds

LCC produced an initial library set of ~112k molecules, which was designed in partnership with Medchemica, using MMPA and their grand rule database. The library was also designed in order to ensure a good range of functionality was incorporated.

We then decided on the criteria upon which to optimise the library:

Physicochemical and CNS penetration criteria were selected based on published literature (e.g. Ro3), experience (solubility > 1 miliM) and targeting the CNS (MPO >4).

  • MPO score devised by Pfizer:
  • CNS penetration required
  • Guidelines suggested - different to Lipinski’s
  • MPO score - probability of CNS penetration
  • 74% CNS drugs have MPO score > 4
  • 6 key physicochemical parameters (logP, logD, TPSA, MW, HBD, HBA, pKa) drive library design

Final set of criteria:

  • Calculated aqueous solubility > 1 milliM
  • MPO score ≥ 4
  • AlogP ≤ 3
  • Molecular weight ≤ 300
  • #H bond donors ≤ 3
  • #H bond acceptors ≤ 3
  • PSA ≤ 60 Å2
  • #Rotable bonds ≤ 3

Library Properties

Histograms of LCC Compounds
LCC Fragments Graph

Results: Out of the initial set of 43226 compounds, 12630 (29%) successfully met all of the criteria.


MW
Solubility (mM)
AlogP
#H Bond Donors
#H Bond Acceptors
MPO
Average
193.93 147.67
0.92
0.85 2.57
5.05
SD
33.2
387.3
1.0 0.7 0.6
0.5

A library of ~13k small, fragment like, highly soluble, CNS penetrant compounds has been designed.