|
 |
Non-antibacterial Tetracyclines
An impressive body of recently published literature
and clinical trial results have shown that the tetracycline compounds
minocycline and doxycycline possess potent anti-inflammatory activity. While
the mechanism is still not fully understood, work underway at Paratek has
provided hints to this mechanism. 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, stroke/ischemia, retinopathy, acne, arthritis, asthma, COPD,
atherosclerosis, allergy and dry eye. Paratek can selectively synthesize
compounds with antibacterial, non-antibacterial, anti-inflammatory or any
combination of these activities.
Targeted areas of development include:
-
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. This effort follows the recent publication of very
favorable clinical data with minocycline (reference 26). Paratek’s novel
compounds offer the potential to show improved activity but without the side
effects associated with broad spectrum antibiotics, which can be a problem with
long-term use of minocycline. Paratek established a Collaborative Research and
License Agreement with Serono SA in October 2004 (now MerckSerono) to develop
novel and improved tetracycline derived compounds for MS. Paratek presented
data on its novel non-antibacterial tetracycline derivatives in the EAE model
in October 2004. Lead candidate compounds for preclinical development have been
designated, and preclinical testing is being conducted in anticipation of
starting Phase 1 trials.
-
Rheumatoid Arthritis (RA) - Based upon validating studies in
clinical literature for the use of tetracyclines, Paratek has placed a high
priority on efforts to exploit opportunities in a variety of inflammatory and
other diseases. Paratek is actively optimizing novel tetracycline compounds in
a variety of arthritis and inflammatory animal models and has shown that its
novel tetracycline derivatives possess improved anti-inflammatory properties in
animal models of RA. A lead is expected to be selected in early 2008.
-
Spinal Muscular Atrophy (SMA) - Reports in the literature suggest
that drugs from the tetracycline class may interact with ribosomal targets to
facilitate RNA splicing. A screening campaign against a spinal muscle atrophy
RNA splicing assay has been completed, 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. Paratek is working
to identify leads for preclinical development. This program represents a new
drug development platform targeting modulation of RNA splicing with
tetracycline derived analogues.
-
Acute Respiratory Distress Syndrome (ARDS) - Paratek is also
exploring the use of its novel tetracycline derivatives in ARDS. Up to 75,000
patients in the U.S. each year develop ARDS, usually from a traumatic injury or
a complication of a variety of other life threatening conditions. Once full
blown ARDS develops, the condition is usually fatal. Novel tetracyclines have
shown promise in in vivo models, and Paratek is searching for a lead
compound that could be advanced in preclinical drug studies.
-
Stroke - Paratek is evaluating novel tetracyclines in established
models of acute inflammatory ischemia/stroke. Stroke is a leading killer in the
U.S. and developed countries around the world, and no adequate therapy exists
to treat or prevent stroke. 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 of stroke. In vivo proof of principle with
novel tetracycline derivatives has been achieved, and further lead development
is underway.
Other anti-inflammatory applications of Paratek's novel
tetracycline derivatives are in the exploratory stage.
|
