Solid-phase chemistry, photolabile protecting groups, and photolithography have been combined to achieve light-directed, spatially addressable parallel chemical synthesis to yield a highly diverse set of chemical products. Binary masking, one of many possible combinatorial synthesis strategies, yields 2n compounds in n chemical steps. An array of 1024 peptides was synthesized in ten steps, and its interaction with a monoclonal antibody was assayed by epifluorescence microscopy. High-density arrays formed by light-directed synthesis are potentially rich sources of chemical diversity for discovering new ligands that bind to biological receptors and for elucidating principles governing molecular interactions. The generality of this approach is illustrated by the light-directed synthesis of a dinucleotide. Spatially directed synthesis of complex compounds could also be used for microfabrication of devices.

A series of 1,3,5-triazine-based estrogen receptor (ER) modulators that are modestly selective for the ERbeta subtype are reported. Compound 1, which displayed modest potency and selectivity for ERbeta vs ERalpha, was identified via high-throughput screening utilizing an ERbeta SPA-based binding assay. Subsequent analogue preparation resulted in the identification of compounds such as 21 and 43 that display 25- to 30-fold selectivity for ERbeta with potencies in the 10-30 nM range. These compounds profile as full antagonists at ERbeta and weak partial agonists at ERalpha in a cell-based reporter gene assay. In addition, the X-ray crystal structure of compound 15 complexed with the ligand binding domain of ERbeta has been solved and was utilized in the design of more conformationally restrained analogues such as 31 in an attempt to increase selectivity for the ERbeta subtype.

Smoking involves heating a drug to form a mixture of drug vapor and gaseous degradation products. These gases subsequently cool and condense into aerosol particles that are inhaled. Here, we demonstrate rapid and reliable systemic delivery of pure pharmaceutical compounds without degradation products through a related process that also involves inhalation of thermally generated aerosol. Drug is coated as a thin film on a metallic substrate and vaporized by heating the metal. The thin nature of the drug coating minimizes the length of time during which the drug is exposed to elevated temperatures, thereby preventing its thermal decomposition. The vaporized, gas-phase drug rapidly condenses and coagulates into micrometer-sized aerosol particles. For the commonly prescribed antimigraine drug rizatriptan, inhalation of these particles results in nearly instantaneous systemic drug action.