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

Autor:	Shrinidhi A; Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States., Dwyer TS; Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States., Scott JA; Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States., Watts VJ; Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States.; Purdue Institute for Drug Discovery, West Lafayette, Indiana 47907, United States.; Purdue Institute for Integrative Neuroscience, 207 South Martin Jischke Dr., West Lafayette, Indiana 47907, United States., Flaherty DP; Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States.; Purdue Institute for Drug Discovery, West Lafayette, Indiana 47907, United States.; Purdue Institute for Integrative Neuroscience, 207 South Martin Jischke Dr., West Lafayette, Indiana 47907, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2024 Oct 24; Vol. 67 (20), pp. 18290-18316. Date of Electronic Publication: 2024 Oct 15.
DOI:	10.1021/acs.jmedchem.4c01645
Abstrakt:	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 Ca 2+ /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 IC 50 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.
Databáze:	MEDLINE
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