Sitagliptin Januvia

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Year of introduction: 2006 (Merck); Drug category: Dipeptidyl peptidase-4 (DPP-4) inhibitor; Main uses: For treatment of type 2 diabetes by enhancing the body's own ability to lower elevated blood sugar levels. It is used as a monotherapy as well as an add-on therapy along with other oral diabetes medications such as metformin or thiazolidinediones (e.g., pioglitazone); Related drugs: Vildagliptin (Galvus).

Since there are about 200 million people worldwide who have type 2 diabetes (see metformin on page 60), and no medicines for reversing or curing this disease, the discovery of molecules that correct the various underlying biochemical abnormalities is of great importance.

The incretins are naturally occurring peptide hormones that play a major role in the glucose-insulin pathway that is central to type 2 diabetes.1 They signal the P-cells in the pancreas to release insulin and the a-cells to suppress glucose release from the liver, the latter by lowering the production of glucagon (also a peptide hormone). The most relevant incretins are glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). These incretins, which are produced by and released from the gut, do not last long in the body since they are rapidly inactivated by an enzyme called dipeptidyl peptidase-4 (DPP-4), which cleaves a two amino acid segment from the amino end (called the N-terminus) of the protein.2 In a healthy person the synthesis of incretins peaks after each meal. The incretin process can be impaired in type 2 diabetics in two ways: (1) GLP-1 levels are decreased or (2) the response to GIP is diminished. It follows that blood glucose levels could be downregulated by blocking the enzymatic activity of DPP-4.

Several DPP-4 inhibitors are now in pharmaceutical development. Sitagliptin (Januvia, Merck) was approved by the FDA for human use as an antidiabetic agent in late 2006. This agent may be used as monotherapy or combined with metformin, glipizide, or pioglitazone, as determined to be optimum for an individual patient.

An important aspect of the drug discovery process with these agents was the achievement of high selectivity for inhibition of DPP-4 over several other structurally related dipeptidyl peptidases that function to cleave other proteins in the body. High selectivity was essential to minimizing side effects. Of course, the optimized structure also had to jump over the usual hurdles of oral absorption, metabolic stability, attainment of an effective concentration of unbound drug in serum, and freedom from other undesired activities. It seems likely that DPP-4 inhibitors will become an important class of antidiabetic agents. The figure below shows the crystal structure of DPP-4 with sitagliptin (red) bound in the active site.3

1. Lancet 2006, 368, 1696-1705; 2. Ann. Pharmacother. 2007. 41, 51-60; 3. J. Med. Chem. 2005, 48, 141-151 (1X70); Refs. p. 83

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