Lead generation using pharmacophore mapping and three-dimensional databasesearching: Application to muscarinic M-3 receptor antagonists

By using a pharmacophore model, a geometrical representation of the feature s necessary for molecules to show a particular biological activity, it is p ossible to search databases containing the 3D structures of molecules and i dentify novel compounds which may possess this activity. We describe our ex periences of establishing a working 3D database system and its use in ratio nal drug design. By using muscarinic M-3 receptor antagonists as an example , we show that it is possible to identify potent novel lead compounds using this approach. Pharmacophore generation based on the structures of known M -3 receptor antagonists, 3D database searching, and medium-throughput scree ning were used to identify candidate compounds. Three compounds were chosen to define the pharmacophore: a lung-selective M-3 antagonist patented by P fizer and two Astra compounds which show affinity at the M-3 receptor. From these, a pharmacophore model was generated, using the program DISCO, and t his was used subsequently to search a UNITY 3D database of proprietary comp ounds; 172 compounds were found to fit the pharmacophore. These compounds w ere then screened, and 1-[2-(2-(diethylamino)ethoxy)phenyl]-2-phenylethanon e (pA(2) 6.67) was identified as the best hit, with N-[2-(piperidin-1-ylmet hyl)cycohexyl]-2-propoxybenzamide (pA(2) 4.83) and phenylcarbamic acid 2-(m orpholin-4-ylmethyl)cyclohexyl ester (pA(2) 5.54) demonstrating lower activ ity. As well as its potency, 1-[2-(2-(diethylamino)ethoxy)phenyl]-2-phenyle thanone is a simple structure with limited similarity to existing M-3 recep tor antagonists.