Pyrazolo-Pyrimidinones with Improved Solubility and Selective Inhibition of Adenylyl Cyclase Type 1 Activity for Treatment of Inflammatory Pain

  • J Med Chem. 2024 Oct 24;67(20):18290-18316. doi: 10.1021/acs.jmedchem.4c01645.
Annadka Shrinidhi  1 ,  Tiffany S Dwyer  1 ,  Jason A Scott  1 ,  Val J Watts  1  2  3 ,  Daniel P Flaherty  1  2  3
Affiliations
  • 1. Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States.
  • 2. Purdue Institute for Drug Discovery, West Lafayette, Indiana 47907, United States.
  • 3. Purdue Institute for Integrative Neuroscience, 207 South Martin Jischke Dr., West Lafayette, Indiana 47907, United States.
PMID: 39404162 DOI: 10.1021/acs.jmedchem.4c01645
Abstract

Adenylyl cyclase isoform 1 (AC1) is considered a promising target for treating inflammatory pain. Our group identified the pyrazolyl-pyrimidinone scaffold as potent and selective inhibitors of CA2+/CaM-mediated AC1 activity; however, the molecules suffered from poor aqueous solubility. The current study presents a strategy to improve aqueous solubility of the scaffold by reduction of crystal packing energy and increasing rotational degrees of freedom within the molecule. Structure-activity and property relationship studies identified the second generation lead 7-47A (AC10142A) that demonstrated and AC1 IC50 value of 0.26 μM and aqueous solubility of 74 ± 7 μM. After in vitro ADME characterization, the scaffold advanced to in vivo pharmacokinetic evaluation, demonstrating adequate levels of exposure. Finally, 7-47A exhibited antiallodynic efficacy in a rat complete Freund's Adjuvant model for inflammatory pain showing improvement over previous iterations of this scaffold. These results further validate AC1 inhibition as a viable therapeutic strategy for treating chronic and inflammatory pain.

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