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Development of Small Molecule Antagonists of PAR-2 for treatment of asthma

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41HL160424-01
Agency Tracking Number: R41HL160424
Amount: $283,387.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: NHLBI
Solicitation Number: PA20-265
Solicitation Year: 2020
Award Year: 2021
Award Start Date (Proposal Award Date): 2021-09-01
Award End Date (Contract End Date): 2022-03-31
Small Business Information
Orinda, CA 94563-1852
United States
DUNS: 117611839
HUBZone Owned: No
Woman Owned: Yes
Socially and Economically Disadvantaged: No
Principal Investigator
 (951) 827-2871
Business Contact
Phone: (951) 660-6652
Research Institution
PO BOX 210158, ROOM 510
TUCSON, AZ 85721-0158
United States

 Nonprofit College or University

ABSTRACT: Current treatments for asthma largely are aimed at reducing exacerbations by
directly treating airway inflammation. While successful in a subset of patients, asthma
exacerbations remain a significant cause of morbidity and mortality and can result in airway
injury, lung function decline and death. Exacerbations in more severe asthmatics are of
particular concern, as health care costs and lost productivity account for $21 billion/year in US
annual health care expenditures. Thus, there is a critical need to develop new therapies to be
used in the treatment of asthma. Protease-activated receptor-2 (PAR-2) is a G-protein-coupled
receptor activated by serine proteases released from asthma-inducing allergens (e.g. German
cockroach, dust mites and the fungus Alternaria alternata), as well as by mast cell tryptase,
human airway trypsin, membrane bound TMPRSS2 and neutrophil elastase. Activated of PAR-2
via allergens or agonists results in complex cellular signaling (b-arrestin and Gaq-Ca2+) that
contribute to the physiological response. Using genetically modified animals, we have shown
that PAR-2/b-arrestin signaling can lead to detrimental outcomes (e.g., cytokine production,
leukocyte infiltration, epithelial hyperplasia, mucus secretion and airway hyperresponsivenes)
while PAR-2/ Gaq-Ca2+ pathways can be beneficial (e.g., broncho-relaxation). Our decade-long
ligand-identification program has resulted in some of the most potent and selective PAR-2
agonists and the first full PAR-2 antagonist, C391. Further, we have shown that C391 can
reduce the detrimental A. alternata-induced asthma indicators in pre-clinical models. Recently,
we have identified several novel small molecule PAR-2 antagonists, including the b-arrestin-
selective antagonist C781 that is a promising candidate for targeting only the detrimental effects
of PAR-2 in the airway. Our central hypothesis is that b-arrestin-selective antagonism of PAR-2
will reduce allergen-induced asthma indicators that lead to exacerbations. The first objective of
this Phase I STTR proposal is to demonstrate the first small molecule biased antagonistic PAR-
2 ligand (C781) can effectively limit allergen-induced asthma indicators in a pre-clinical mouse
model. The second objective is to modify C391 and C781 for pulmonary-specific targeting while
retaining/improving on their PAR-2 antagonistic function. Our company, PARMedics, was
founded on the principle that we can create custom modifications with improved
pharmacokinetic properties and stability for the development of this new class of asthma
therapeutics.PROJECT NARRATIVE: The objective of this Phase I proposal is to develop a protease-
activated receptor-2 small molecule antagonist that can reduce/eliminate allergen-induced
inflammatory effects in the lung. Through collaborations with our company, PARMedics, and the
University of Arizona, we plan to develop a new class of therapeutics for asthma and other
inflammatory lung diseases.

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

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