NONIMMUNOSUPPRESSIVE CYCLOSPORIN ANALOG MOLECULES

“An emerging class of multifunctional drugs showing promise as anti-viral, anti-inflammatory, and cytoprotective agents”

NOVEL CYCLOPHILIN INHIBITORS: THE NICAM PLATFORM

ISOTECHNIKA PHARMA INC. is a leader in the synthesis and development of cyclosporin (CsA) analogues. ISOTECHNIKA PHARMA‘S discovery-stage NICAM compounds are an extensive platform of proprietary non-immunosuppressive CsA-based cyclophilin inhibitors for the treatment of cyclophilin-mediated disorders. This includes:

• Inhibiting replication of hepatitis C virus, HIV, and SARS coronavirus
• Preventing cell death in heart attacks, stroke, brain and spinal cord injuries, and neurodegenerative disorders
• Blocking inflammatory reactions in asthma, arthritis, multiple sclerosis, and vascular disease

The range of in vitro and in vivo screening procedures used by ISOTECHNIKA PHARMA and the diversity of biophysical and biochemical characteristics of the NICAMs, allows for the optimization and tailoring of cyclophilin inhibitors for a particular indication. 

THE NICAM COMPOUNDS

THE NICAM compounds are synthesized from CsA using a novel non-complex synthetic process which produces high affinity cyclophilin inhibitors and removes the powerful immunosuppression.

The similarities to CsA, which has been in clinical use for nearly a quarter-century, significantly mitigates the risk for clinical development. However, NICAMs surpass CsA in other important ways, such as:

• No off-target side effects and complications associated with immunosuppression
• More potent cyclophilin inhibition 
• Better bioavailability
• Potential for improved brain penetration

CYCLOPHILIN INHIBITORS and MULTIFUNCTIONALITY in DISEASE TREATMENT

The cyclophilins are a family of evolutionarily conserved, multifunctional proteins that are found in most cells. Cyclophilins normally are supportive biological molecules with enzymatic activity, but in many disease conditions their actions are deleterious, participating in virus replication, mitochondrial dysfunction, oxidative and calcium-mediated cell death, leukocyte invasion, and other pathogenic mechanisms.

A large body of animal model data across many indications has demonstrated the therapeutic potential of cyclophilin inhibition, leading to clinical trials with positive outcomes in hepatitis C, myocardial infarction, and traumatic brain injury. Efficacy in hepatitis C is based on the involvement of cyclophilins in hepatitis C virus replication. Cyclophilin inhibition also has been shown to block in vitro replication of HIV and coronaviruses (ubiquitous pathogens of humans and livestock, including the SARS agent), opening the door to a new class of broad-spectrum antiviral compounds. In myocardial infarction, traumatic brain injury and other degenerative conditions, cyclophilin inhibition protects mitochondria and reduces cell death. Protection is afforded by blocking the opening of mitochondrial permeability transition pores, a terminal event in many pathological signaling cascades. Cyclophilins also are found extracellularly, where they function as leukocyte chemoattractants. Inhibiting cyclophilin-mediated chemoattraction holds much promise in the treatment of inflammatory diseases such as chronic asthma and arthritis.

Most diseases have multiple pathogenic pathways, so rather than targeting a single mechanism, new treatments should aim to neutralize multiple pathways. Owing to the multiple intracellular and extracellular roles which cyclophilin plays, a single NICAM drug can be genuinely multifunctional in such conditions as myocardial infarction, stroke, and multiple sclerosis where both cell death and inflammatory pathways are involved in disease progression and outcome.

ISOTECHNIKA PHARMA believes that the NICAM compounds are uniquely suited for treatment of the full range of cyclophilin-mediated disorders, with the additional benefits of a broad therapeutic window, uncomplicated manufacturing and multifunctional action