Sitagliptin
[CAS 486460-32-6]

Identification

• Classification: API >> Circulatory system medication >> Regulating blood lipids
• Name: Sitagliptin
• Synonyms: (3R)-3-Amino-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one
• Molecular Formula: C₁₆H₁₅F₆N₅O
• Molecular Weight: 407.32
• CAS Registry Number: 486460-32-6
• EC Number: 690-730-1
• SMILES: C1CN2C(=NN=C2C(F)(F)F)CN1C(=O)C[C@@H](CC3=CC(=C(C=C3F)F)F)N

Properties

• Density: 1.6±0.1 g/cm³ Calc.^*
• Boiling point: 529.9±60.0 °C 760 mmHg (Calc.)^*
• Flash point: 274.3±32.9 °C (Calc.)^*
• Solubility: DMSO: 10 mM (Expl.)
• Index of refraction: 1.59 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS05;GHS07;GHS08 Danger
• Risk Statements: H302-H318-H373
• Safety Statements: P260-P264-P264+P265-P270-P280-P301+P317-P305+P354+P338-P317-P319-P330-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Acute toxicity	Acute Tox.	4	H302
Specific target organ toxicity - repeated exposure	STOT RE	2	H373
Serious eye damage	Eye Dam.	1	H318
Specific target organ toxicity - single exposure	STOT SE	3	H335
Eye irritation	Eye Irrit.	2	H319
Eye irritation	Eye Irrit.	2A	H319
Skin irritation	Skin Irrit.	2	H315

chemBlink Chemical Story

Sitagliptin, CAS 486460-32-6, is the free-base form of the selective dipeptidyl peptidase-4 (DPP-4) inhibitor developed at Merck and marketed in salt form as Januvia. Its discovery grew from a biological idea rather than from modification of an older diabetes drug. By the late 1990s, glucagon-like peptide-1 (GLP-1) had emerged as an attractive way to improve glucose-dependent insulin secretion, but the peptide is rapidly inactivated by DPP-4. Merck therefore began a DPP-4 inhibitor program in 1999 to reproduce part of the GLP-1 effect with an orally active small molecule.

The medicinal-chemistry program initially explored several inhibitor classes. Researchers eventually developed a beta-amino triazolopiperazine series that combined potent DPP-4 inhibition with high selectivity and oral activity. Sitagliptin emerged from this work with a distinctive fluorinated structure containing a trifluorophenyl group and a trifluoromethyl-substituted triazolopyrazine system. FDA GSRS identifies the free compound as C16H15F6N5O and CAS 486460-32-6.

DPP-4 normally cleaves and inactivates incretin hormones including GLP-1 and GIP. Inhibiting the enzyme prolongs active incretin signaling after meals. Because incretin effects on insulin secretion are glucose-dependent, this approach offered a mechanistically different route to controlling blood glucose compared with directly stimulating insulin release regardless of glucose concentration.

The U.S. FDA approved sitagliptin phosphate as Januvia in 2006 for treatment of type 2 diabetes. The distinction between molecular and pharmaceutical identity matters: CAS 486460-32-6 refers to sitagliptin itself, while marketed material has commonly been supplied as a phosphate salt or hydrate form. Those forms deliver the same active sitagliptin framework but have different solid-state identities.

Sitagliptin became the first approved member of the DPP-4 inhibitor class in the United States. Its story shows how understanding hormone metabolism can generate a drug target, and how target-based medicinal chemistry can then convert that biological insight into a stable oral small molecule.

References:
1. Thornberry NA, Weber AE. Discovery of JANUVIA (Sitagliptin), a selective DPP-IV inhibitor for the treatment of type 2 diabetes. Curr Top Med Chem. 2007;7:557-568. PMID 17352677.
2. U.S. FDA GSRS, Sitagliptin, UNII QFP0P1DV7Z, CAS 486460-32-6.
3. U.S. FDA, Januvia (sitagliptin phosphate) approval information, 2006.

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