11 Years of Cyanopyrrolidines as DPP-IV Inhibitors

Abstract

Cyanopyrrolidines (cyanopyrrolidides, pyrrolidine-2-nitriles, prolinenitriles) as inhibitors of the serine protease dipeptidyl peptidase IV (DPP-IV, DP IV, CD26, EC 3.4.14.5) were first reported in 1995. The interest in this compound class grew immensely when DPP-IV was discovered as a target for the treatment of type 2 diabetes. The research on cyanopyrrolidines cumulated in the discoveries of vildagliptin (LAF237, NVP-LAF237) and saxagliptin (BMS-477118). These compounds entered Phase III clinical trials in 2004 and 2005, respectively, and an application for market approval has been filed for vildagliptin in 2006. Today cyanopyrrolidines are, as judged by the numbers of patent applications, the most prominent of several series of DPP-IV inhibitors, and have the potential to become valuable medicines for type 2 diabetes in the near future. This review summarizes some historical aspects of the discovery of cyanopyrrolidine DPP-IV inhibitors, and then focuses mainly on structure-activity-relationships, the evolution of different subseries, the possibilities to improve on the chemical instability that is associated with this compound class, and on the discoveries of vildagliptin and saxagliptin. Within this context, the properties of individual compounds and results from biological studies are discussed. The rationale of DPP-IV inhibition, clinical data, and the relevance of selectivity over related proteases are extensively reviewed in other contributions to this issue of Curr. Top. Med. Chem., and are therefore only very briefly touched.

Drugs for the Treatment of Type II Diabetes: A Visit to the Past and a Look to the Future

“…A formação desta ligação covalente é, no entanto, reversível, resultando em inibidores competitivos com cinética de dissociação bastante lenta. 37,38 Mais recentemente, novos inibidores da enzima DPP-4 foram introduzidos na clínica, a exemplo do derivado xantínico Linagliptina (28, Tradjenta®, Boehringer Ingelheim; Figura 7), aprovado pelo FDA em 2011, e do derivado pirimidínico Alogliptina (29, Nesina®, Takeda; Figura 7), aprovado para uso clínico inicialmente no Japão, em 2010, e posteriormente nos EUA, no ano de 2013. 37 Figura 7.…”

Inhibitors of cathepsin K: a patent review (2004 – 2010)

“…Although, no cysteine protease inhibitors have yet reached the market, the successful application and safety of the reversible warhead approach has been effectively demonstrated by the reversible serine protease inhibitor vildagliptin. The anti-hyperglycemic agent vildagliptin (Galvus Ò , Novartis, Basel, Switzerland), which was introduced to the European market in 2008, forms a reversible covalent imidate ester adduct with the hydroxyl group of the active-site serine in dipeptidyl peptidase-4 (DPP-4) to prevent the inactivation of the incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (gastric inhibitory peptide) [20]. It should be noted though that DPP-4 has a deep lipophilic pocket combined with several …”

Exploration of the DPP-4 inhibitors with a focus on saxagliptin

“…Substrate-like DPP-4 inhibitors usually have an electrophilic group that can interact either covalently or noncovalently with the active binding site of the enzyme [18]. Cyanopyrrolidines are competitive inhibitors of the DPP-4 enzyme and form reversible covalent bonds with the catalytically active serine hydroxyl (Ser630) site [19,20]. Examples of cyanoprirolidines are vildagliptin and saxagliptin.…”