400-fold safer than cannabidiol and exhibited an in vitro profile consistent with improved oral bioavailability. " />
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Kinney WA, McDonnell ME, Zhong HM, et al. Discovery of KLS-13019, a Cannabidiol-Derived Neuroprotective Agent, with Improved Potency, Safety, and Permeability. ACS Med Chem Lett. 2016;7(4):424-8doi: 10.1021/acsmedchemlett.6b00009.
Kinney, W. A., McDonnell, M. E., Zhong, H. M., Liu, C., Yang, L., Ling, W., Qian, T., Chen, Y., Cai, Z., Petkanas, D., & Brenneman, D. E. (2016). Discovery of KLS-13019, a Cannabidiol-Derived Neuroprotective Agent, with Improved Potency, Safety, and Permeability. ACS medicinal chemistry letters, 7(4), 424-8. https://doi.org/10.1021/acsmedchemlett.6b00009
Kinney, William A, et al. "Discovery of KLS-13019, a Cannabidiol-Derived Neuroprotective Agent, with Improved Potency, Safety, and Permeability." ACS medicinal chemistry letters vol. 7,4 (2016): 424-8. doi: https://doi.org/10.1021/acsmedchemlett.6b00009
Kinney WA, McDonnell ME, Zhong HM, Liu C, Yang L, Ling W, Qian T, Chen Y, Cai Z, Petkanas D, Brenneman DE. Discovery of KLS-13019, a Cannabidiol-Derived Neuroprotective Agent, with Improved Potency, Safety, and Permeability. ACS Med Chem Lett. 2016 Feb 10;7(4):424-8. doi: 10.1021/acsmedchemlett.6b00009. eCollection 2016 Apr 14. PMID: 27096053; PMCID: PMC4834656.
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ACS Med Chem Lett. 2016 Feb 10;7(4):424-8. doi: 10.1021/acsmedchemlett.6b00009. eCollection 2016 Apr 14.

Discovery of KLS-13019, a Cannabidiol-Derived Neuroprotective Agent, with Improved Potency, Safety, and Permeability.

ACS medicinal chemistry letters

William A Kinney, Mark E McDonnell, Hua Marlon Zhong, Chaomin Liu, Lanyi Yang, Wei Ling, Tao Qian, Yu Chen, Zhijie Cai, Dean Petkanas, Douglas E Brenneman

Affiliations

  1. KannaLife Sciences , 3805 Old Easton Road, Doylestown, Pennsylvania 18902, United States.
  2. PharmaAdvance, Inc. , 6 Dongsheng West Road, Building D1, Jiangyin, Jiangsu Province, P. R. China.

PMID: 27096053 PMCID: PMC4834656 DOI: 10.1021/acsmedchemlett.6b00009

Abstract

Cannabidiol is the nonpsychoactive natural component of C. sativa that has been shown to be neuroprotective in multiple animal models. Our interest is to advance a therapeutic candidate for the orphan indication hepatic encephalopathy (HE). HE is a serious neurological disorder that occurs in patients with cirrhosis or liver failure. Although cannabidiol is effective in models of HE, it has limitations in terms of safety and oral bioavailability. Herein, we describe a series of side chain modified resorcinols that were designed for greater hydrophilicity and "drug likeness", while varying hydrogen bond donors, acceptors, architecture, basicity, neutrality, acidity, and polar surface area within the pendent group. Our primary screen evaluated the ability of the test agents to prevent damage to hippocampal neurons induced by ammonium acetate and ethanol at clinically relevant concentrations. Notably, KLS-13019 was 50-fold more potent and >400-fold safer than cannabidiol and exhibited an in vitro profile consistent with improved oral bioavailability.

Keywords: cannabidiol; hepatic encephalopathy; neuroprotection

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