Lohocla Development Pipeline
Kindolor®: Brief Summary
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 which would reduce 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 it produces significant anti-hyperalgesia properties in four animal models of chronic pain. The metabolic fate profile of Kindolor is 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. Following a second non-rodent species, one-month toxicity study, we plan to open a US IND and begin clinical testing.
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
principalfunctions 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% of the world’s population. The primary pharmaceuticals for treatment of chronic
pain have been natural or synthetic opioids and the use of opioids for pain treatment has resulted in what
has been called an “epidemic” of
opioid abuse, addiction and lethal overdoses. We have, through a process of rational drug design, generated
a new chemical entity (NCE) and have given it the name Kindolor. Kindolor is a non-opiate, non-addicting
molecule that was developed specifically to simultaneously control the aberrant activity of three 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 and as
an inhibitor of NMDA receptors that act to magnify pain signals
(Fig. A). We have generated 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 generated evidence that this broad
range of efficacy is a result of the multi-target engagement by Kindolor. We have generated the initial
evidence for the safety (high TI) of Kindolor and its uneventful metabolism. Additional attractive features
of Kindolor are that it can prevent the development of chronic pain if given soon after tissue injury. And
if combined with low doses of opiates, Kindolor produces a substantial “opiate sparing” effect
through synergistic actions with the opiates. To bring Kindolor to the public, we are proposing to complete
the pre-clinical studies necessary for an IND application to
the FDA and, if the IND is approved, the completion of a Phase 1a and 1b, first in human, study of the
safety of our compound, and then a Phase 2a study of efficacy on pain of osteoarthritis. The satisfactory
completion of a pre-IND meeting with the FDA will allow for expedient completion of the IND application.
Given approval of the IND application, we propose to complete the Phase 1a and 1b study and the Phase 2a
study. In all, our goal is to bring our compound to a full Phase 2 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 for treatment of chronic pain. This new chemical entity, 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. In this grant application we are requesting funds to
complete cGMP synthesis and GLP studies necessary for an IND application to the FDA, and given the FDA
approval of the IND status, the completion of the first in human, Phase I clinical studies for safety and
Phase 2a studies of efficacy to bring our medication to chronic pain sufferers.