Discovery of JANUVIA™ (Sitagliptin), a Selective Dipeptidyl Peptidase IV Inhibitor for the Treatment of Type2 Diabetes.

Abstract

The emergence of glucagon-like peptide 1 (GLP-1) as a well validated approach to the treatment of type 2 diabetes and preclinical validation of dipeptidyl peptidase IV (DPP-4) inhibition as an alternate, oral approach to GLP-1 therapy prompted the initiation of a DPP-4 inhibitor program at Merck in 1999. DPP-4 inhibitors threo- and allo-isoleucyl thiazolidide were in-licensed to jump start the program; however, development was discontinued due to profound toxicity in rat and dog safety studies. The observation that both compounds inhibit the related proline peptidases DPP8 and DPP9 led to the hypothesis that inhibition of DPP8 and/or DPP9 could evoke severe toxicities in preclinical species. Indeed, the observed toxicities were recapitulated with a selective dual DPP8/9 inhibitor but not with an inhibitor selective for DPP-4. Thus, medicinal chemistry efforts focused on identifying a highly selective DPP-4 inibitor for clinical development. Initial work in an alpha-amino acid series related to isoleucyl thiazolidide was discontinued due to lack of selectivity; however, SAR studies on two screening leads led to the identification of a highly selective beta-amino acid piperazine series. In an effort to stabilize the piperazine moiety, which was extensively metabolized in vivo, a series of bicyclic derivatives were prepared, culminating in the identification of a potent and selective triazolopiperazine series. Unlike their monocyclic counterparts, these analogs typically showed excellent pharmacokinetic properties in preclinical species. Optimization of this series led to the discovery of JANUVIA (sitagliptin), a highly selective DPP-4 inhibitor for the treatment of type 2 diabetes.

Reversible Inactivation of Human Dipeptidyl Peptidases 8 and 9 by Oxidation

“…The DPIV enzyme family consists of DPIV, fibroblast activation protein (FAP), DP8 and DP9. Much interest has been focused on the enzyme activity of DPIV, and its inhibition as a type 2 diabetes therapy [11], but DPIV has roles in metabolism, immune responses, the endocrine system and cancer biology. FAP has roles in liver and cancer biology [12].…”

?-Amino Acids: Role in Human Biology and Medicinal Chemistry - A Review

“…Sitagliptin comprises an (R)-3-amino-4-(2,4,5-trifluorophenyl) butanoic acid subunit [42]. Many further derivatives of sitagliptin have been synthetized and tested as potential antidiuretic drugs ( Figure 13) [43].…”

"In-Silico Design, Synthesis and Pharmacological Evaluation of Pyrrolidine-2-Carbonitrile Derived Anti-Diabetic Agents"

“…Intense research in this field resulted in useful Sitagliptin and vildagliptin DPP-4 inhibitors and other are in pre-registration, e.g., saxagliptin and alogliptin 9 . Variety of review articles are currently out there that cover numerous aspects of DPP-4 inhibitors extensively [10][11][12][13][14][15] . Clinical data reveals that the recent DPP-IV inhibitor offers many prospective advantages, counting no or less weight gain and no risk of hypoglycemia.…”