Discovery of KLS-13019, a Cannabidiol-Derived Neuroprotective Agent, with Improved Potency, Safety, and Permeability.
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.
KannaLife Sciences , 3805 Old Easton Road, Doylestown, Pennsylvania 18902, United States.
William A
WA
Kinney
KannaLife Sciences , 3805 Old Easton Road, Doylestown, Pennsylvania 18902, United States.
Mark E
ME
McDonnell
PharmaAdvance, Inc. , 6 Dongsheng West Road, Building D1, Jiangyin, Jiangsu Province, P. R. China.
Hua Marlon
HM
Zhong
PharmaAdvance, Inc. , 6 Dongsheng West Road, Building D1, Jiangyin, Jiangsu Province, P. R. China.
Chaomin
C
Liu
PharmaAdvance, Inc. , 6 Dongsheng West Road, Building D1, Jiangyin, Jiangsu Province, P. R. China.
Lanyi
L
Yang
PharmaAdvance, Inc. , 6 Dongsheng West Road, Building D1, Jiangyin, Jiangsu Province, P. R. China.
Wei
W
Ling
PharmaAdvance, Inc. , 6 Dongsheng West Road, Building D1, Jiangyin, Jiangsu Province, P. R. China.
Tao
T
Qian
PharmaAdvance, Inc. , 6 Dongsheng West Road, Building D1, Jiangyin, Jiangsu Province, P. R. China.
Yu
Y
Chen
PharmaAdvance, Inc. , 6 Dongsheng West Road, Building D1, Jiangyin, Jiangsu Province, P. R. China.
Zhijie
Z
Cai
KannaLife Sciences , 3805 Old Easton Road, Doylestown, Pennsylvania 18902, United States.
Dean
D
Petkanas
KannaLife Sciences , 3805 Old Easton Road, Doylestown, Pennsylvania 18902, United States.
Douglas E
DE
Brenneman
cannabidiol; hepatic encephalopathy; neuroprotection