Privileged structures: applications in drug discovery.

Over the past 15 years the privileged structure concept has emerged as a fruitful approach to the discovery of novel biologically active molecules. Privileged structures are molecular scaffolds with versatile binding properties, such that a single scaffold is able to provide potent and selective ligands for a range of different biological targets through modification of functional groups. In addition, privileged structures typically exhibit good drug-like properties, which in turn leads to more drug-like compound libraries and leads. The net result is the production of high quality leads that provide a solid foundation for further development. The identification of privileged structures will be discussed, emphasizing the importance of understanding the structure-target relationships that confer "privileged" status. This understanding allows privileged structure based libraries to be targeted at distinct target families (e.g. GPCRs, LGIC, enzymes/kinases). Privileged structures have been successfully exploited across and within different target families and promises to be an effective approach to the discovery and optimization of novel bioactive molecules. The application of the privileged structure approach, both in traditional medicinal chemistry and in the design of focused libraries, will be discussed with the aid of illustrative examples.

New syntheses of the C,D-ring pyrromethenones of phytochrome and phycocyanin.

Pyrromethenone 7, the C,D-ring segment of phytochrome (Pr, 4), has been prepared in an efficient fashion employing three new strategies. Each of these has potential advantages for the synthesis of labeled material. Our first approach is related to the Gossauer synthesis, with the difference that strong alkali is avoided in the condensation of the C- and D-ring components 8 and 17. The key silyloxypyrrole 17 was readily prepared on multigram scales beginning with inexpensive butyrolactone (10). A second synthesis began with 2-acetylbutyrolactone (41). The key steps involved conversion of 41 to the Z-enoltriflate 42, followed by Pd(0)-catalyzed coupling with trimethylsilylacetylene, p-chlorophenylselenide ring opening, and finally, amidation to afford the ring-D synthon 45 having the proper geometry and oxidation state for conversion to 7. Sonogashira coupling of 45 with the iodopyrrole 22, followed by oxidative elimination, and F(-)-induced 5-exo-dig cyclization of the resultant pyrroloalkyne 47, then completed the synthesis. In similar fashion, we have also prepared pyrromethenone 6, the C,D-ring segment of phycocyanin (2).

Substituted 3-(2-benzoxazyl)-benzimidazol-2-(1H)-ones: a new class of GABA(A) brain receptor ligands.

A novel class of potent benzodiazepine receptor (BZR) ligands has been designed and synthesized aided by molecular modeling of known benzodiazepine ligands such as CGS-8216 and the use of known pharmacophore models.