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Protease-activated-receptor-2 antagonists for treatment of migraine pain

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41NS127637-01A1
Agency Tracking Number: R41NS127637
Amount: $310,351.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: 106
Solicitation Number: NS20-009
Solicitation Year: 2020
Award Year: 2023
Award Start Date (Proposal Award Date): 2023-01-15
Award End Date (Contract End Date): 2023-12-31
Small Business Information
41593 Winchester Rd. Suite 220
Temecula, CA 92590-4841
United States
DUNS: 117611839
HUBZone Owned: No
Woman Owned: Yes
Socially and Economically Disadvantaged: No
Principal Investigator
 (951) 660-6652
Business Contact
Phone: (951) 660-6652
Research Institution
Office of Research and Innovation, AD15 800 WEST CAMPBELL ROAD
RICHARDSON, TX 75080-3021
United States

 Nonprofit College or University

Migraine affects over 36 million people in the US, particularly those of working age (18-55 years), negatively
impacting workplace productivity and presenting an enormous healthcare burden. For almost half of those who
suffer from migraine, current treatments fail to provide relief and have limited ability to reverse pain once it has
started. The most effective medications either require injection (CGRP antibodies) or are associated with
increased cardiovascular risk (triptans). In addition, none of these provide complete relief to most patients.
Migraine pain results from aberrant activation of specialized neurons that innervate the meninges, resulting in
the release of neurotransmitters that cause local inflammation, and trigger a pain signal to central terminals in
the brainstem. This signal is then carried to higher brain centers resulting in the perception of pain, and the
continued presence of inflammatory mediators in the periphery perpetuate this painful signal.
Protease-activated-receptor-2 (PAR2) is a membrane receptor that is activated by enzymes that are released
from immune cells in the meninges, over the course of a migraine attack. Its activation contributes to migraine
pain at multiple points: increasing the release of excitatory neurotransmitters; lowering the threshold for activation
of pain transmitting neurons; and promoting the synthesis of additional inflammatory mediators. The main site of
action of PAR2 is in the peripheral nerve terminals. This is in contrast to the targets of current migraine
therapeutics that also play major roles in the central nervous system. We have identified two small molecule
inhibitors of PAR2 that reduce migraine-like pain in animals. Significantly, these molecules act without crossing
the blood brain barrier (BBB), even when administered after the onset of an attack. In this proposal, we aim to
modify the chemical scaffold of our lead compound to improve its potential for oral delivery. We will use a high
throughput screen to examine inhibition of receptor activation and downstream signaling pathways. Selected
compounds will then be tested for favorable pharmacokinetics (e.g., stability, oral bioavailability, and low BBB
penetrance) and pain-reduction in animal models of migraine. The overall goal is to identify a lead compound
that can be delivered orally to move into IND-enabling studies for the treatment of migraine pain.

* Information listed above is at the time of submission. *

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