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The SARfaris: GPCR, Kinase, ADME

Tuesday, 17 May 2011

New Drug Approvals 2011 - Pt. XIII Linagliptin (TradjentaTM)

ATC code : A10BH05
On May 2nd, the FDA approved Linagliptin (BI-1356, trade name Tradjenta, ATC code A10BH05, ChEMBL ID 237500 NDA 201280), a dipeptidyl peptidase-4 (DPP-4) inhibitor, to treat type II diabetes (OMIM: 125853). Linagliptin has been approved for monotherapy or in combination with other medications, in conjunction with exercise and dietary modification. Due to a malfunction in production of or response to insulin, patients with type II diabetes suffer from high blood glucose levels.

By inhibiting DPP-4 (Uniprot P27487, OMIM: 102720, EC number, a cell surface glycoprotein receptor, Linagliptin stabilizes the level of two of its substrates, the intecrins GLP-1 and GIP, gastrointestinal peptide hormones which stimulate insulin release from beta cells of the Islets of Langerhans.

Linagliptin has been shown to have a high affinity (Ki 1 nM) for DPP-4 in cell-based fluorescence assays, and to be highly selective. DPP-4 exists in soluble form (aminoacids 39-766) or with a N-terminal single-anchor domain, linking the extracellular domain to the cell membrane. There are several homodimeric crystal structures available, e.g. PDB 1J2E.
The -gliptin USAN stem covers DPP-IV inhibitors, and there are a number already launched (e.g. Saxagliptin, Sitagliptin and Vildagliptin) and many others in clinical trials/registration (e.g. Alogliptin (SYR-322, TAK-322), Carmegliptin (R-1579, Ro-4876904), Dutogliptin (PHX-1149), Gosogliptin (PF-734200), and Denagliptin (GSK-823903)). There are a very large number of others at earlier stages of development include R-1438, BI-1356, NVP-DPP-728, GRC-8200, SK-0403, P-32/98, PSN-9301, TS-021, R-1499, PSN-357, DP-893, LC-150444, BMS-686117, TAK-100, BMS-477128, ABT-279, ARI-2243, SSR-162339, ER-319711 Ro-0730699, NN-7201, MP-513, KRP-104, E-3024, and ALS-2-0426 (AMG-222).

There is a previous ChEMBL-og monograph available for Saxagliptin.

Linagliptin (systematic name 8-[(3R)-3-aminopiperidin-1-yl]-7-(but-2-yn-1-yl)-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]-3,7-dihydro-1H-purine-2,6-dione) has the chemical formula C25H28N8O2, molecular mass of 472.54 g/mol. ), AlogP of 2.1 and is fully Rule-of-five compliant.

Tradjenta is dosed as a 5 mg tablet, once daily (equivalent to a daily dose of 10.6 umol).
After a single administration, a maximum concentration (Cmax) of 8.9 nmol/L is reached after Tmax=1.5 h. Linagliptin has a long terminal half-life (>100 h) and steady-state plasma concentrations are reached after the third daily dose. At steady state, Cmax is increased by a factor of ~1.3 as compared to the single administration. The mean apparent volume of distribution (Vd) is approximately 1110 L.

Tradjenta is distributed by Boehringer Ingelheim and marketed by Boehringer Ingelheim and Eli Lilly and Company. In Europe the tradename is Trajenta.

The full prescribing information can be found here and the product website, here.

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