Targeted libraries for hit identification
Design and production of focussed libraries of small molecules targeted at:
- CNS indications
- Oncology indications, including kinases and epigenetic targets
LCC’s targeted libraries are designed in partnership with MedChemica and Dr Neil Berry from the department of chemistry, University of Liverpool:
LCC’s targeted libraries are synthesised by our teams of expert chemists in the UK and China. Our wealth of experience in asymmetric synthesis and heterocyclic chemistry allows for efficient synthesis of novel molecules based upon heterocyclic cores:
Our libraries can be designed and synthesised on an exclusive or non-exclusive basis, depending on the exact requirements of our customers.
Design of a CNS Focussed Fragment 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 heterocylce. 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 CNS Drugs
LCC produced an initial library set of ~11,000 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 solubility > 1 milliM
- MPO score > 4
- AlogP < 3
- Molecular weight < 300
- #H bond donors < 3
- #H bond acceptors < 3
Out of the initial set of ~11,000 compounds, ~3,000 (~27%) successfully met all of the criteria.
A library of ~3000 small, fragment like, highly soluble, CNS penetrant compounds has been designed.
As can be seen below, the ~3000 compounds sit in a favourable area of MPO/logP/Solubility space – all compounds have MPO score >4 (green).
In terms of shape, the 3000 compound library show a similar distribution in shape to currently approved CNS compounds. Concentrated near the rod-disc axis but with considerable 3D character (towards sphere point).