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MONMOUTH JUNCTION, NJ, United States

Patent
Signum Biosciences | Date: 2012-08-03

Among other things, the present invention provides novel compounds capable of effectively inhibiting inflammatory responses that are mediated by G-proteins or GPCRs in neutrophils, macrophages and platelets. In particular, the compounds of the present invention act as inhibitors of edema, inhibitors of erythema and inhibitors of MPO (myeloperoxidase), pharmaceutical compositions containing the same compounds and the use thereof for the treatment of diseases that may benefit from edema, erythema and MPO inhibition, such as inflammation (acute or chronic), asthma, autoimmune diseases, and chronic obstructive pulmonary disease (COPD) (e.g., emphysema, chronic bronchitis and small airways disease, etc.), inflammatory responses of the immune system, skin diseases (e.g., reducing acute skin irritation for patients suffering from rosacea, atopic dermatitis, seborrheic dermatitis, psoriasis), irritable bowel syndrome (e.g., Chrons disease and ulcerative colitis, etc.), and central nervous system disorders (e.g., Parkinsons disease).


Patent
Signum Biosciences | Date: 2012-12-20

The present invention relates to pharmaceutical, cosmetic and cosmeceutical topical compositions containing polyisoprenyl-protein inhibitor compounds and methods useful in the promotion of healthy epithelium and the treatment of epithelial-related conditions


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 1.57M | Year: 2009

DESCRIPTION (provided by applicant): Isoprenylcysteine (IPC) analogs modulate heterotrimeric G-protein coupled receptor (GPCR) signaling pathways, representing a novel class of topical anti-inflammatory compounds whose action is restricted to the site of application. Studies performed in the Phase I proposal demonstrate that IPC analogs have a wide spectrum of anti-inflammatory activities with a superior safety profile to glucocorticoids. Signum's proof of concept IPC analog, AFC, inhibited erythema (redness) in a double blind, vehicle controlled cosmetic human use study. More potent IPC analogs serve as attractive drug development candidates for reducing erythema and treating rosacea. Several IPC analogs identified from Signum's screening program are attractive candidates for preclinical development. The proposed Phase II research plan will identify one lead compound and two backups for preclinical development and will establish the analytical methods, process development and formulation that are necessary. Furthermore, these studies will determine the preclinical safety profile of the lead compound by performing metabolic, pharmacokinetic, toxicology and safety pharmacology studies. Together, the data generated from these studies will allow Signum to prepare and submit an IND for treatment of rosacea. PUBLIC HEALTH RELEVANCE: Rosacea is a common, chronic cutaneous condition afflicting millions of individuals. FDA approved treatments have yielded mixed results, often leaving patients with significant levels of facial redness. Successful pharmaceutical development of IPC analog anti-inflammatories will provide an important additional, and potentially better, therapeutic option for people suffering from rosacea redness.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 356.92K | Year: 2010

DESCRIPTION (provided by applicant): N-acetyl-S-famesyl-L-cysteine (AFC) and its derivatives (isoprenylcysteine (IPC) analogs) represent a novel class of topically absorbed NSAIDs whose activity is restricted to the site of application with no detectable systemic effects and no adverse affects such as skin atrophy or inhibition of wound healing. In a double- blinded, vehicle-controlled cosmetic human use study; AFC was shown to inhibit chronic skin erythema. Based on our previous work we hypothesize we can identify more potent and selective 2nd generation IPC compounds to effectively treat chronic inflammatory skin diseases associated with erythema. If it is determined that IPC analogs inhibit cytokine release induced by inflammatory or other mediators, reduce skin erythema more potently than AFC and a predictive relationship is established between in vitro and in vivo activity for IPC analogs, the feasibility of the project will have been demonstrated. Prof. Richard D. Granstein, Chairman of the Department of Dermatology at the Weill Medical College of Cornell University, and Dr. John Seykora, assistant Professor of the Department of Dermatology at the University of Pennsylvania, will contribute to this effort to successfully complete the Aims of this grant. This will lead in Phase II to a program to identify and develop novel pharmaceutical leads for the treatment of inflammatory skin diseases associated with erythema such as eczema (e.g. atopic dermatitis, seborrheic dermatitis) and rosacea. PUBLIC HEALTH RELEVANCE: Treatment for chronic inflammatory skin diseases characterized by a prominent degree of erythema, remains largely unsatisfactory and the development of more effective therapies represents a great unmet medical need. The paucity of relevant experimental models for these diseases hinder drug development efforts; thus, new treatments and screening methods to test for efficacy are required. Successful development of this novel class of topical non-steroidal anti-inflammatories will provide an important additional, and potentially better, therapeutic option for people suffering from rosacea and eczema (e.g. atopic dermatitis, seborrheic dermatitis).


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 324.72K | Year: 2010

DESCRIPTION (provided by applicant): Abnormal hyperphosphorylation of tau plays an important role in Alzheimer's disease (AD) and other tauopathies. Current therapeutic approaches with focus on tau kinases (e.g. GSK-3, MAPK, cdk5, CK-1, PKA, CaMKII) are hindered by multiple and redundant tau phosphorylation pathways. In contrast, protein phosphatase-2A (PP2A) is the major tau phosphatase accounting for ~70% of tau dephosphorylation, and recent research shows that its expression and activity are down-regulated in AD. PP2A activity is governed by reversible carboxyl-methylation, thus inhibiting demethylation might be a promising intervention strategy to restore healthy tau phosphorylation levels. Building a screening platform around this hypothesis, we identified a small molecule SIG1012, which reduces p-tau levels in N2a cells in a dose-dependent manner and is orally efficacious in reducing p-tau in wild type mice. Preliminary pharmacological data suggests that SIG1012 has highly favorable safety and toxicology profiles. The proposed Phase I research plan is critical to validating PP2A as a pharmaceutical target for effective intervention in AD by a small molecule. It outlines specific steps for the proposed proof of concept studies of efficacy in animal models of AD. The critical 3xTg-AD mouse and (AAV)-I2 CTF rat experiments will be carried out in collaboration with Dr. Khalid Iqbal, a world- renowned expert on the role of tau in neurodegenerative diseases. Successful completion of this research proposal will lead in Phase II to formal preclinical development of SIG1012 as the first-in-class PP2A modulating agent for treatment of AD and other tauopathies. ) PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is a progressive and fatal brain disease that afflicts over 5 million Americans today and over 27 million people worldwide. Current treatments of AD are largely unsatisfactory and development of more effective therapies represents a great unmet medical need. Successful development of this novel class of phosphoprotein modulators will provide an important additional, and potentially better, therapeutic option for people suffering from AD.

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