Chemistry
The core chemistry technology provides synthesis of mimetics in a
relatively short number of steps and bearing any side-chain groups
(except proline in some positions).
The tripeptide mimetic 1 forms the basis of the turn mimetics. The
important feature of Mimetica’s technology is the ability to
selectively produce every one of the sixteen possible diastereomers
of 1 having any sidechain combination with only minor changes to the
procedure or different starting materials. To the best of our knowledge
there is currently no equivalent technology.
Fast Synthesis of Mimetics
The synthesis of mimetics lacking the R1 group (in 1)
is illustrated in Scheme 1 below. The procedures are 4 or 6 steps – literature
methods for similarly complex mimetics are typically much longer. A
process synthesis of a drug based on this method would be 6-7 steps
from simple starting materials.
Scheme 1
Allyl Dipeptides – Key Intermediates
The ability to produce all the diastereomers of 1 for the full range
of peptide sidechains relies on the discovery by Mimetica that allylated
dipeptides 8 can be formed using B-allyl boranes. This selective reaction
allows C-C bond formation in the presence of typical peptide protection
groups including amides, carbamates and esters.
Scheme 2
Compound 8 can be formed as a single distereomer with appropriate
chiral ligands on boron. With B-allyl 9BBN the product diastereomers
are formed in an 8:2 ratio, the major diastereomer being as indicated
in 8.
Synthesis of Mimetics from Allyl Dipeptides
The allyl dipeptides 8 are converted to tripeptide mimetics as described
in Schemes 3 and 4. The key feature of this chemistry is the reductive
amination of aldehydes 11. Under normal conditions (presence of acid)
the reaction proceeds with inversion of configuration to give 90% of
13. However, when the reaction is conducted in the absence of acid
this isomerization is prevented and the configuration is retained to
yield 12.
Scheme 3
Thus, compounds 12 and 13 are selectively accessible depending on
reaction conditions. The other three chiral centres in the mimetics
are derived from the (amino acid) starting materials and are not racemised
during the synthesis. Therefore all four chiral centres can be individually
and separately controlled giving access to all sixteen possible diastereomers
of 1.
Scheme 4
The cyclisation reaction of 12 or 13 to 14 can be effected by heating
or deprotection / coupling (depending on the specific protecting chemistry
used).
A process chemistry approach to the production of compounds of type
1 would take 9-11 steps from typical industrial starting materials.
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Also in this section:
• OptiMim™
• Alpha-Helix Mimetics
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