Objective: optimising a known lead by systematic exploration of substituents around a core scaffold.

Typical project: Focused screening of small-sized libraries (< 500 compounds) on a macromolecular target for which hits/leads have already been identified.

Technology: The focused library is designed either by applying pharmacophoric constraints to our screening collection of commercially available compounds or by using SLF_Libmaker® 1-2 – the latter enables the enumeration of small-sized libraries via combinatorial assembly of linkers, pharmacophoric features and user-defined scaffolds.

Competitive advantages: Our SLF_Libmaker® technology ensures rapid, stepwise optimization of a known lead while maximising the chances of obtaining better compounds at each iteration cycle (design-enumeration-synthesis). The recent application of this process to the optimisation of a phosphodiesterase inhibitor yielded a subnanomolar inhibitor with a 900-fold increase in affinity relative to the starting lead.1

Reference
1 - Krier et al. (2005) Design of small-sized libraries by combinatorial assembly of linkers and functional groups to a given scaffold: Application to the structure-based optimization of a phosphodiesterase 4 inhibitor. J. Med. Chem., 2005, 48, 3816-3822
2 - Kirkpatrick, P (2005) Best of both worlds. Nature New Drug Discov. 4, 540