Lohocla Research Corporation rationally designed a novel small molecule named Kindolor for treatment of
chronic pain syndromes. The molecule simultaneously reduces the over-activity of NMDA (NR1-NR2B) receptors and the Nav1.7 and
Nav1.8 sodium channels in chronic pain syndromes. Kindolor has negligible blood brain barrier
penetrance, reducing deleterious CNS side effects. Thus, Kindolor’s actions are confined to the
peripheral nervous system. Kindolor’s proof of concept has been established and shows that Kindolor
produces significant anti-hyperalgesia effects in four animal models of chronic pain. Kindolor is
metabolized via glucuronidation and hydroxylation. No genotoxic effects of Kindolor have been noted. Acute
dosing levels 50 times higher than doses producing therapeutic effects produced no overt signs of toxicity,
and we estimate the therapeutic index for Kindolor to be greater than 50. Lohocla will submit an IND application to the FDA and begin clinical testing in the second half
of 2022.
Fig. A
Illustrates the interaction of NMDA receptors with TRPV1 receptors in the sensory terminals of
nociceptors. NMDA receptors are co-localized with the TRPV1 receptors, and the activation of the
NMDA receptors by glutamate released into the surrounding milieu upon local irritation,
generates a phosphorylation cascade via PKC and PKA. The end-product of this cascade is the
phosphorylation of TRPV1 and an increase in its activity in generating pain signals.
Kindolor inhibits NMDA receptor function and significantly dampens this enhanced excitability.
Illustrates a schematic of the delta opiate receptor (DOR) coupled to adenylyl cyclase (AC)
through the Gi protein trimer. Activation of DOR at peripheral nerve endings leads to
dissociation of the Gi trimer and the Gαi subunit inhibits AC activity,
lowering cellular cAMP, while the βɤ subunits inhibit voltage sensitive calcium channels and
stimulates the GIRK type potassium channels. These actions reduce the potential for nociceptor
depolarization and pain signal generation. Kindolor acts as an agonist at DORs.
Focuses attention on the conduction of pain information from the nociceptor terminals.
Nav1.7 channels have a low (hyperpolarized) activation threshold, and this activation
initially (prior to responding with an action potential) produces a change in membrane potential
which can activate the Nav1.8 channels, which quickly respond with an action
potential. Both the Nav1.8 and Nav1.7 action
potentials are propagated to the dorsal root ganglia where the cell bodies of the sensory
neurons reside. Kindolor inhibits both the Nav1.8 (more
potently) and Nav1.7 channels and thus depresses both the excessive signal generation
by Nav1.7 and increased conduction by both Nav1.8 and Nav1.7 in
patients suffering from chronic pain.
Illustrates events happening within the sensory dorsal root ganglia. Within the dorsal
root ganglia, a close juxtaposition is evident between two cell bodies of the sensory neurons
and satellite glial cells. The satellite glial cells are “sandwiched” between the two cell
bodies of the sensory neurons, and this structure is called a “sandwich synapse.” One of the
principal functions of the sandwich synapse is to amplify the signals reaching the dorsal root
ganglia. As illustrated, this occurs via release of ATP by the cell body of the initially
activated neuron. The ATP activates the purinergic receptors (P2Y2) on the satellite glial
cells, and the satellite glial cells respond by releasing glutamate. The glutamate activates
NMDA receptors on the neighboring (juxtaposed) sensory neuron cell body and instigates
depolarization and conduction of signal to the spinal
cord.
Kindolor, by inhibiting the NMDA receptor on cell bodies of the sensory neurons prevents the
amplification of the signal mediated by the sandwich synapses.
Illustrates a schematic of the pentameric GABA-A receptor which gates chloride flux across a
neuronal membrane. In the presence of low levels of GABA, Kindolor acts as a positive allosteric
modulator (PAM) to promote channel opening. Kindolor acts at a novel site at the interface of
the α+β- subunits extracellular domain (this is illustrated as a blue dot
at the top of the rendition of the pentameric arrangement of the GABA-A receptor; top right of
Box 5). Activation of GABA-A receptors in the DRG has been shown to inhibit signal propagation
through the DRG.
Background
Over 100 million adults in the U.S. suffer from intermittent or constant chronic pain, and chronic pain
affects at least 10 percent of the world’s population. The primary pharmaceuticals for treatment of
chronic pain have been natural or synthetic opioids. However, the use of opioids for pain treatment has
resulted in what has been called an “epidemic”
of opioid abuse, addiction, and lethal overdoses. Through a process of rational drug design, Lohocla
Research has generated a new chemical entity (NCE) that we have named Kindolor. Kindolor is a
non-opiate, non-addicting molecule that was developed specifically to simultaneously control the aberrant
activity of several key targets on the peripheral sensory system that are integral in the development and
propagation of chronic pain. Kindolor acts as an inhibitor of the pain-propagating Nav1.7 and
Nav1.8 sodium channels as well as the TRPV1 and NMDA receptors that act to conduct and to magnify pain signals
(Fig. A). We have developed a process to synthesize Kindolor at 99 percent purity. In our pre-clinical
studies we have demonstrated the efficacy of Kindolor to reduce or eliminate chronic pain generated in five
animal models at doses compatible with use of Kindolor in humans. We have collected evidence that this broad
range of efficacy is a result of the multi-target engagement by Kindolor. We have obtained the initial
evidence for the safety (high TI) of Kindolor and its uneventful metabolism. Supplementary attractive
features of Kindolor are that it can prevent the development of chronic pain if given soon after tissue
injury. Additionally, if combined with low doses of opiates, Kindolor produces a substantial “opiate
sparing” effect through synergistic actions with the opiates. Lohocla Research is working to bring
Kindolor to the public. An IND application is in process, and
Phase 1 trials are planned for 2022-3, followed by Phase 2 trials for efficacy in treating diabetic
neuropathy. In all, our goal is to bring our compound to a Phase 3 ready stage for licensing or partnering
with a Pharma company willing and able to bring the medication to the chronic pain sufferer.
Public Health Relevance Statement
The U.S. and other countries around the world are facing “dual crises of pain and opioid addiction.”
Lohocla Research Corporation has responded to the opioid crisis and medication development challenge by
designing, synthesizing, and demonstrating, in pre-clinical studies, the efficacy and safety of a
non-opiate, non-addictive new chemical entity (NCE) for treatment of chronic pain. This NCE, called
Kindolor, has significant additional benefits of being able to prevent the development of chronic
pain if administered soon after tissue injury, including post-operative conditions. Kindolor also has a
highly significant “opiate sparing” effect in conditions that may require the use of opiates,
since Kindolor demonstrates a strong synergistic effect with morphine. Given the FDA approval of our IND
status, we will complete first-in-human, Phase I clinical studies for safety and Phase 2a studies of
efficacy to bring our medication to chronic pain sufferers.