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MATCH™
(Macrocyclic Template Chemistry) is
Tranzyme Pharma’s proprietary drug discovery and medicinal
chemistry technology. Tranzyme has successfully used this
chemistry technology to produce several developmental and
clinical stage drug candidates. With MATCH™,
for the first time, the construction of synthetic libraries
of drug-like, orally administered macrocyclic compounds can be
conducted in a highly predictable and efficient manner.
MATCH™ is a chemistry breakthrough with broad application
to accelerate drug discovery.
MATCH™ is based on the development of proprietary small molecule macrocycles.
Tranzyme’s macrocycles are a distinct class of small molecules with defined and predictable shapes. Although
many macrocyclic compounds from natural sources or with complex chemistries have been successfully developed
as marketed drugs, Tranzyme’s compounds represent the first completely synthetic and systematically synthesized
collection of macrocycles. MATCH™ allows, for the first time, the efficient and predictable construction of
synthetic libraries of these molecules. In the past, the potential of macrocycles as attractive drugs has been
largely underutilized. Tranzyme now makes these unique compounds available for pharmaceutical drug discovery.
MATCH™ is a rich source of novel drug candidates.
MATCH™ compounds mimic the favorable binding characteristics of proteins and peptides such as
tight receptor binding for high potency and selectivity, while eliminating the drawbacks
associated with biomolecules — poor metabolic stability, low oral bioavailability, lack of
membrane permeability, high manufacturing costs, and antigenicity.
MATCH™ macrocycles ensure tighter binding and improved potency.
In order to attain high affinity and to bind selectively to a targeted receptor, a
successful mimetic must reproduce both the functionality and the orientation of the
receptor-bound peptide ligand. As shown in the figure below, Tranzyme macrocycles
incorporate three recognition moieties locked in a defined, cyclic, three-dimensional
structure by a proprietary non-peptide chemical fragment called a tether, having a
molecular weight of 100-200. The recognition moieties originate from either natural
or non-natural amino acids. MATCH™ enables Tranzyme to vary these tethers in order
to control and modulate spatial orientation. While the recognition moieties provide
the elements that interact with targeted receptor, the tethers define and control
their unique conformation, ensuring tighter binding and improved potency. MATCH™ also
enables the incorporation of recognition elements other than amino acids to explore
the effects of other functionalized building blocks...
A demonstration of the effects of the proprietary
non-peptide tether (T1, T2, T3) on molecular shape and display of recognition elements (X, Y, Z).
Tranzyme has synthesized more than 100 tethers and used them for optimization. The defined
topology often leads to significant drug activity of initial hits.
MATCH™ possesses significant strategic advantages over traditional methods of drug discovery.
- Accelerated hit-to-lead-to-clinic progression due to simultaneous and controlled variation of critical parameters to optimize compound affinity and selectivity.
- Robust, reliable chemistry that can be easily scaled-up.
- Simultaneously scans diversity in composition and in conformation, resulting in improved activity and selectivity.
- Effective for multiple targets - appropriate for a wide array of pharmaceutically interesting systems.
- Can be used directly to generate lead compounds or employed as a template from which further modifications can be performed.
- Employs individual building blocks designed to enhance potential bioactivity and to modulate and optimize any observed activity.
- Low number of rotatable bonds, which favors high oral bioavailability and successful progression through the clinic.
- Provides metabolic and proteolytic stability and improved PK-ADME profile.
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