Chronic pain is a major health concern that costs the United States more than $635 billion per year. Unfortunately, drugs used for the management of chronic pain either have limited effectiveness or often lead to addiction, most notably in the case of opioid analgesics. That the pharmaceutical industry is retreating from studying novel pain therapeutics due to the enormous financial risk is also concerning. These observations indicate an essential need to identify new agents acting on unique targets for the treatment of chronic pain. Emerging neurobiological, genetic, and preclinical studies have suggested that neuronal adenylyl cyclase type I (AC1) may be a new target for the treatment of chronic pain. However, reported inhibitors of AC1 have significant liabilities most importantly being lack of selectivity over other AC isoforms. There is a significant need for potent and selective AC1 inhibitors to pharmacologically validate AC1 as a viable target for the treatment of chronic pain. To this end our team has identified a novel class of pyrimidinone-based inhibitors that are both potent and selective toward AC1 with sub-micromolar cellular efficacy in reducing cyclic AMP output from AC1. Our efforts to optimize potency, pharmacokinetic properties, and <i>in vivo</i> analgesic efficacy of this class of molecules in a mouse model for chronic pain are described.

Development of adenylyl cyclase type 1 inhibitors for the treatment of chronic pain

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.