Paul R. Menard

Applications of N-BOC-diamines for the solution phase synthesis of ketopiperazine libraries utilizing a Ugi/De-BOC/Cyclization (UDC) strategy

Abstract This communication reveals a novel application of the ‘so-called’ convertible isonitrile for the solution phase generation of ketopiperazine libraries. Use of mono N-BOC diamines in the Ugi multi-component reaction (MCR), followed by BOC removal and base treatment (a ‘3 step, 1-pot procedure’) affords ketopiperazines in good yield. The generality of this procedure was further explored revealing novel routes to dihydroquinoxalinones and 1,4-benzodiazepines respectively

Chemistry Space Metrics in Diversity Analysis, Library Design, and Compound Selection

DiverseSolutions software was used to generate a “universal” chemistry space that can be used as a standard for profiling most structural sets of interest. A nonlinear method for assigning structures to bins within chemistry space descriptors was developed. This allows the use of chemistry spaces scaled to include all structures within a set, while maintaining a reasonable distribution of structures within bins and providing target percentage cell occupancies. The universal chemistry space and nonlinear binning method were validated using random structures extracted from the Beilstein database. The approach was then used, in conjunction with other diversity analyses, for diverse subset selection and comparison of compound collections.

RATIONAL SCREENING SET DESIGN AND COMPOUND SELECTION : CASCADED CLUSTERING

The use of cascaded clustering is reported. This technique was developed to permit the application of Jarvis-Patrick clustering based on structural fingerprints to large chemical databases, while keeping the maximum cluster size and the number of singletons produced at reasonable levels. The basis for the algorithm, its implementation, and validation are described. In the first part of the paper, the approach is used to create a representative subset of compounds for biological testing from the corporate compound repository. A variation of the method is then used for the comparison of relatively large databases. Finally, compound selection using cascaded clustering is shown to be complementary to the Diverse Property-Derived approach, which is based on partitioning by six molecular descriptors.

Synthesis and diversity analysis of lead discovery piperazine-2-carboxamide libraries

A Lead Discovery Library ofpiperazine-2-carboxamide derivatives was produced forgeneral screening. This paper discloses two novelsolid phase synthetic routes used to produce 15 000single compounds via the Irori directed sortingtechnique. Computational methods such as reagentclustering and library profiling were used to maximizereagent diversity and optimize pharmacokineticparameters. The results of a four center pharmacophoreanalysis revealed the added diversity gained by usingtwo independent synthetic routes.