DPP-4 inhibitors

Gliptins (DPP-4 inhibitors) Sitagliptin Inhibit DPP-46 enhance prandial insulin secretion Oral... 

In order to jump-start internal efforts on the DPP-4 inhibitor program, L-threo-(2S,3S)-isoleucyl thiazolidide 3 (Figure 2) and its alio (2S,3R) stereoisomer were... 

When the medicinal chemistry program began in late 1999, nearly all of the DPP-4 inhibitors known in the literature were derived from a-amino acids, and those lacking an electrophile such as the isoleucyl thiazolidides were considerably less potent than those containing a nitrile or boronic acid such as DPP728. One report suggested that cyclohexylglycine derived inhibitors showed improved potency... 

As some of the toxicity observed with DPP-8/9 inhibitors 4 and 7 in predinical species suggested a potential immune system role, we hypothesized that the immunological effects observed with historical DPP-4 inhibitors [14] might be due to inhibition of DPP-8/9 instead of DPP-4 as initially reported. Sure enough, when these historical compounds were assayed at DPP-8/9 and DPP-4, they possessed more potent intrinsic inhibition at DPP-8/9 than at DPP-4 [20]. Furthermore, we demonstrated that DPP-8/9 inhibitor 7 is able to attenuate proliferation and IL-2 release in human in vitro models of T-cell activation, while a selective DPP-4 inhibitor does not. Recent tissue distribution studies also suggest a role for DPP-8 in the immune system [25]. 

Table 17.2 Off-target activities of cyclohexylglycine DPP-4 inhibitors (ICso s, nM).

Further efforts in related series afforded structurally similar DPP-4 inhibitors such as acid 13 (E. Parmee, unpublished results), thiazole 14 [35] and cyclopentylglycine 15 (Figure 17.3) [36], Although 15 did not show improved selectivity over DPP-8/9,13 and 14 showed some improvement in selectivity over these counterscreens. Nevertheless, none of these compounds exhibited sufficient selectivity to merit further pursuit zwitterion 13 also possesses low oral bioavailability in rats (F < 1%). Consequently, focus in the a-amino acid series shifted to acyclic derivatives. 

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