The Discovery of the Dipeptidyl Peptidase-4 (DPP4) Inhibitor Onglyza: From Concept to Market - Accounts in Drug Discovery Case Studies in Medicinal Chemistry - page 7

Figure 1.4 Rationale for generation of conformationally restricted DPP4 inhibitors.
nitrilo-pyrrolidines were deemed to be highly attractive, but were reported to
exhibit modest pharmacokinetic duration of action and suffered from chemical
instability. 33,34 In solution, the proximal amino group attacks the nitrile
functionality (see Figure 1.3), eventually leading to the intermediate cyclic
imidate 13 and ultimately the diketopiperzine 14, both of which are inactive
versus DPP4. Addressing this issue was viewed as a critical component of the
medicinal chemistry effort due to considerations regarding both the half-life of
the compound in vivo, and for high purity processing of the active pharma-
ceutical ingredient (API) on large scale in a drug manufacturing setting.
From earlier work by Lin et al., 39 it was demonstrated that replacement of
the prolyl amide bond with a fluoroalkene isostere resulted in the generation of
potent DPP4 inhibitor 15 (Figure 1.4). This finding was significant in that it
suggested that the critical prolyl and amino pharmacophores in 16 may be
conformationally locked in an extended arrangement which is favorable for
enzyme inhibition. In addition, because incorporation of the alkene prohibits
intramolecular attack of the amine onto the acyl hydroxamate, the finding
suggested novel paths for inhibitor design to retard intramolecular cyclization.
Taking a cue from earlier work performed at BMS in the design of dual
ACE/NEP inhibitors, 40 we applied the concept of conformationally restricted
dipetide mimetics in our search for novel inhibitor chemotypes. Many of these
cores seemed to possess the critical elements required for DPP4 inhibition,
including a prolyl amide group and a charged amino functionality at the P2
position. It was hoped that locking the inhibitor conformation by this approach
would not only enhance binding anity, but also prevent inactivating cycli-
zation in compounds possessing an electrophilic pharmacophore (e.g. nitrile,
phosphate, etc.) on the proline ring. Unguided by the availability of a DPP4
X-ray crystal structure at that time, our design efforts led to a variety of
different bi- and monocyclic dipetide mimetics, generically represented in
Figure 1.4. Unfortunately, all of the compounds generated in this series were
inactive against DPP4, which we attributed to either incorrect conformational
geometry required for inhibition, or to steric intolerance for substitution on the
proline ring. The latter hypothesis was supported by the poor activity exhibited
by the simple methyl-substituted prolyl derivative 17 as compared to its
unsubstituted counterpart 8. Interestingly, a recent report from Phenomix
disclosing 5,5-fused bicyclic lactams such as 18 as potent DPP4 inhibitors
provides validation for this initial approach. 41