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Non-antibacterial Tetracyclines
An impressive body of recently published
literature and clinical trial results have shown that the tetracycline compounds such as minocycline and
doxycycline possess potent anti-inflammatory activity. While the target is still not fully understood in every case, work
underway at Paratek has provided insights into the mechanism of action. Paratek has created the world's most extensive and
chemically diverse
collection of thousands of tetracycline derivatives, and these compounds also show diverse biologic activity. Paratek
is using this library to identify novel derivatives with improved anti-inflammatory activity. Target diseases for this approach
include multiple sclerosis, rheumatoid arthritis, inflammatory bowel diseases (ulcerative colitis and Crohn’s disease), acne and ischemia
(stroke and AMI).
Outside the anti-inflammatory area, selected Paratek compounds have been found to selectively modulate
RNA splicing. Novel small molecule RNA splice modifiers are being developed in spinal muscular atrophy (SMA) and with other
compounds being explored in Familial Dysautonomia and other rare genetic diseases resulting from RNA splicing disorders.
Paratek selectively synthesizes compounds with antibacterial, non-antibacterial, anti-inflammatory, RNA splice modifying or
any combination of these activities.
Targeted areas of development include:
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Multiple Sclerosis -Paratek is developing orally available non-antibacterial tetracyclines for the treatment
of multiple sclerosis (MS). These compounds are disease-modifying agents to reduce demyelination, relapses and
progression in patients suffering from various forms of MS, including relapsing and remitting MS by inhibiting microglial
activation and neuroprotection. This effort
follows the recent publication of very favorable clinical data with minocycline (reference 26, 27, 28). Paratek’s novel
compounds show potent activity but without the side effects associated with immunosuppressive therapy, which can
be a problem with current therapies. Paratek’s data suggest activity that is better than current treatments. Lead
candidate compounds for preclinical
development have been designated, and preclinical testing is being conducted in anticipation of starting Phase 1 trials.
- Inflammatory Bowel Diseases (IBD) and Rheumatoid Arthritis (RA) -Based upon
validating studies in clinical literature for the use of tetracyclines in MS and RA, Paratek has exploited
opportunities in a variety of inflammatory and other diseases. Paratek has optimized novel tetracycline compounds for
arthritis and inflammatory bowel disease in animal models of RA. A development lead and
back-ups have been selected and preclinical development studies are underway.
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Spinal Muscular Atrophy (SMA) -Reports in the literature suggest that drugs from the tetracycline class
may interact with ribosomal targets to facilitate RNA splicing. Paratek has developed a set of small molecules that
have demonstrated activity in spinal muscle atrophy RNA splicing, and the Company is currently conducting confirmatory
animal studies on novel tetracyclines’ ability to stimulate the splicing of the correct form of SMN protein in vivo.
These lead compounds are currently in preclinical development. This program represents a new drug development
platform targeting modulation of RNA splicing with tetracycline derived analogues. Additionally, Paratek has confirmed
the specificity of activity to SMA splicing and identified separate compounds with an affinity for correcting aberrant
splicing in Familial Dysautonomia.
- Acute Myocardial Infarction (AMI) and Ischemia -Paratek is evaluating novel
tetracyclines in established models of acute inflammatory ischemia/AMI. AMI is a leading killer in the U.S. and developed
countries around the world, and no adequate therapy exists to treat or prevent ischemic disease. A number of studies
in vivo suggest that tetracyclines may offer benefit after a stroke or may be used for prophylaxis in patients
at high-risk. In vivo proof of principle with novel tetracycline derivatives has been achieved, and exploratory
studies have been conducted.
Other anti-inflammatory applications of Paratek's novel
tetracycline derivatives are in the exploratory stage.
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