This presentation will describe the application of Medicinal Chemistry to the development of both potential small and large molecule therapeutics. First, the discovery of telcagepant, a calcitonin gene-related peptide (CGRP) receptor antagonist designed to treat migraine headaches, will be detailed.  The identification of the caprolactam core and optimization of both the regio- and stereochemistry of pendant aryl rings were essential to balancing potency and pharmacokinetics.  These efforts ultimately contributed to the identification of telcagepant, a compound which has demonstrated efficacy for migraine treatment in Phase III clinical trials.  The second portion of the presentation will detail our efforts in development of small interfering RNAs (siRNAs) to facilitate gene silencing.  Efficient delivery of siRNA to the RNA-induced silencing complex (RISC) is an essential requirement for developing siRNA-based therapeutics.  This is a challenging, multi-step process that includes target tissue access, cellular uptake, and entry into the cytoplasm for RISC loading.  Methodology was developed to conjugate multiple functionalities to oligonucleotides to overcome these barriers.  These conjugates were used to validate the importance of linker structure and electronic properties in siRNA delivery.

Medicinal chemistry of small and large molecules: Discovery of telcagepant and development of siRNA therapeutics

244th National Meeting (2012)

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