Optimization of a 1,3,4-oxadiazole series for inhibition of Ca2+/calmodulin-stimulated activity of adenylyl cyclases 1 and 8 for the treatment of chronic pain

Eur J Med Chem. 2019 Jan 15:162:568-585. doi: 10.1016/j.ejmech.2018.11.036.

Jatinder Kaur ¹, Monica Soto-Velasquez ¹, Zhong Ding ¹, Ahmadreza Ghanbarpour ¹, Markus A Lill ², Richard M van Rijn ², Val J Watts ², Daniel P Flaherty ³

Affiliations

1 Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, 575 Stadium Mall Dr, West Lafayette, IN, 47907, USA.
2 Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, 575 Stadium Mall Dr, West Lafayette, IN, 47907, USA; Purdue Institute for Drug Discovery, Purdue University, West Lafayette, IN, 47907, USA; Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN, 47907, USA.
3 Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, 575 Stadium Mall Dr, West Lafayette, IN, 47907, USA; Purdue Institute for Drug Discovery, Purdue University, West Lafayette, IN, 47907, USA; Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN, 47907, USA. Electronic address: dflaher@purdue.edu.

PMID: 30472604 DOI: 10.1016/j.ejmech.2018.11.036

Abstract

Adenylyl cyclases type 1 (AC1) and 8 (AC8) are group 1 transmembrane adenylyl cyclases (AC) that are stimulated by CA²⁺/Calmodulin. Studies have shown that mice depleted of AC1 have attenuated inflammatory pain response, while AC1/AC8 double-knockout mice display both attenuated pain response and opioid dependence. Thus, AC1 has emerged as a promising new target for treating chronic pain and opioid abuse. We discovered that the 1,3,4-oxadiazole scaffold inhibits CA²⁺/calmodulin-stimulated cyclic adenosine 3',5'-monophosphate (cAMP) production in cells stably expressing either AC1 or AC8. We then carried out structure-activity relationship studies, in which we designed and synthesized 65 analogs, to modulate potency and selectivity versus each AC isoform in cells. Furthermore, molecular docking of the analogs into an AC1 homology model suggests the molecules may bind at the ATP binding site. Finally, a prioritized analog was tested in a mouse model of inflammatory pain and exhibited modest analgesic properties. In summary, our data indicate the 1,3,4-oxadiazoles represent a novel scaffold for the cellular inhibition of CA²⁺/calmodulin-stimulated AC1- and AC8 cAMP and warrant further exploration as potential lead compounds for the treatment of chronic inflammatory pain.

Keywords

1,3,4-Oxadiazole; Adenylyl cyclase inhibitors; Chronic pain treatment; Molecular modeling.

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