The Design of Leadlike Combinatorial Libraries

Angew Chem Int Ed Engl. 1999 Dec 16;38(24):3743-3748. doi: 10.1002/(SICI)1521-3773(19991216)38:24<3743::AID-ANIE3743>3.0.CO;2-U.


The optimization of low-potency leads into drugs is often accompanied by an increase in molecular weight (M(r)) and lipophilicity, as a consequence of affinity enhancement. Hits with affinity at µM levels discovered by screening leadlike libraries allow scope for this optimization process, as shown schematically by the distributions of M(r) for a leadlike library (1), oral drugs (2), and a typical combinatorial chemistry library (3). y=percentage with a particular molecular weight.