Preclinical Development of Novel Dual OXR/KOR Antagonists for Treatment of Substance Use Disorder

ABSTRACT (Project Summary)
Substance use disorder (SUD) characterized by the repeated use of an addictive substance leading to loss of intake
control represents a serious public health and socio-economic burden with over 164 million people affected worldwide.
SUD-related costs in the US surpass $750 billion USD annually, with over $272 billion of that attributed to the abuse
of illicit drugs and prescription opioids. Of these, cocaine and related stimulants cause some of the most serious
morbidity. More than 20% of fatal drug overdoses (2018) in the US involved cocaine, representing over 14,666 deaths.
Mortality from cocaine use disorder (CUD) has tripled in the US from 2012 to 2018. Nonetheless, there are currently
no approved drugs for the treatment of CUD, making it a serious global health threat and unmet medical need. Orexin
neuropeptides (OX-A and OX-B) are endogenous ligands for two GPCRs, OX1R and OX2R. Their role in sleep/wake
cycle and arousal has been studied, and the use of OXR antagonists for insomnia has been clinically validated with
marketed drugs for sleep disorders (i.e.: Suvorexant). In addition to circadian cycle modulation, orexins also exert
their effects through actions on the mesocorticolimbic dopamine (DA) system and thus are intricately involved with
motivated behavior, arousal and reward-seeking, key components of addiction behavior. While both OX1R and OX2R
signaling are implicated in the sleep/arousal effects, most or all the attenuation of stress-adaptive responses and
addiction/reward-seeking behavior is attributed to OX1R signaling. First generation OXR antagonists (Suvorexant) are
dual-acting (DORAs), inhibiting both OX1R and OX2R with similar potencies. Recently reported OX1R antagonist tool
compounds tend to be modestly selective for OX1R (~50-fold) but possess poor physical properties. Designing ligands
that can modulate two or more orthogonal signaling pathways simultaneously could provide a synergistic biological
response in complicated disease states like stress-related mood disorders including depression, anxiety, and SUD.
As such, the goal of this application is to develop a series of first-in-class, potent / highly selective OX1R antagonists
(SORAs) as Dual-Targeted Ligands which also modulate other targets - that would provide an innovative treatment
for CUD without the sleep-inducing liabilities seen with existing DORAs. We have already discovered, and patented
potent multi-targeted preclinical small molecule leads with the following profiles: i) Highly Selective (>1000-fold) OX1R
antagonists with dual mechanism of action and ii) OX1R-prefering antagonists which also modulate other targets.
Thus, the 1st Specific Aim of this U01 application is to conduct in vitro pharm profiling studies of 6 selected OX1R-
Dual Targeted leads including microsomal stability, solubility, Caco-2 permeability, MDR1-MDCK efflux ratio,
and plasma & brain protein binding, initiate a med chem multi-parameter lead optimization campaign; select of
up to 6 lead compounds that emerge with optimal overall profiles for in vivo PK/PD studies. The 2nd Specific Aim
is Assess of up to 2-4 emerging compounds with optimal pharmacology and PK/PD profiles in 2 rodent behavioral
models relevant for CUD/SUD. The 3rd Specific Aim is to identify up to 2 leads and a structurally distinct backup
compound which meet pre-defined metrics and perform comprehensive preclinical studies including CYP
Induction, Met ID, transporters Inhibition, CYP Phenotyping, PXR activation, and human hepatocyte stability,
initiate non-GMP scale-ups (50 – 200 g) of up to 2 NCEs for dose range-finding studies to support rat PK/PD.
The 4th Specific Aim: is to identify and select a lead with the best overall profile to be declared as a Clinical
Development Candidate(s) and start all IND-enabling studies.

Grant Number: 1UF1DA054817-01A1
NIH Institute/Center: NIH
Principal Investigator: John Butera