ALENDRONIC ACID: FORMULA, STRUCTURE, PROPERTIES AND USES - CHEMISTRY - 2024

The alendronic acid is an organic compound belonging to the classification of bisphosphonates, specifically to the second generation; These are those that contain nitrogen atoms. This compound, as well as the rest of the bisphosphonates, has a high structural analogy with inorganic pyrophosphate (PPi).

Inorganic pyrophosphate is the product of many synthetic reactions in the body. It is stored in many tissues of the body, and its incorporation into bones has been found to regulate their calcification and mineralization. Alendronic acid, like PPi and bisphosphonates, has a high affinity for hydroxyapatite crystals in bone.

For this reason it is intended as a drug for the treatment of diseases of the same, including osteoporosis. In the pharmaceutical market it is obtained under the trade name Fosamax in its ionic form (alendronate sodium trihydrate), alone or in combination with vitamin D.

The predominant dosage forms are tablets and coated tablets. It is synthesized by heating GABA (4-amino butyric acid) with orthophosphorous acid (H ₃ PO ₃) under an inert nitrogen atmosphere. Phosphorus trichloride (PCl ₃) is then added.

After the steps of adding water, decolorizing the solution with charcoal and diluting it in methanol, the solid alendronic acid is obtained. Finally, the acid is neutralized with NaOH to obtain alendronate sodium.

Formula

The condensed molecular formula of alendronic acid is C ₄ H ₁₃ NO ₇ P ₂. However, the only information that can be extracted from this is the molecular weight of the compound and the number of unsaturations.

The molecular structure is necessarily necessary to discern its physical and chemical properties.

Structure

The upper image shows the molecular structure of alendronate. The red spheres correspond to oxygen atoms, mustards to phosphorous atoms, gray to carbon atoms, white to hydrogen atoms, and the blue sphere to nitrogen.

The structure can be assimilated to a zigzagged letter T, its ceiling being the key to why the compound is considered a bisphosphonate. PPi (O ₃ P ─ O ─ PO ₃) is analogous to the molecular ceiling of T (O ₃ P ─ C (OH) ─ PO ₃), with the only difference that the central atom that joins the phosphate groups for the Bisphosphonates is a bisphosphonic carbon.

In turn, this carbon is linked to a hydroxyl group (-OH). From this carbon emerges an alkyl chain of three methylene units (–CH2 ─), which ends with an amino group (─ NH ₂).

It is the amino group, or any substituent that has a nitrogen atom, responsible for this bisphosphonate belonging to the second or third generation.

In alendronate all the acidic hydrogens (H ⁺) have been given to the medium. Each phosphate group releases two H ⁺, and since there are two groups, a total of four H ⁺ can release the acid; It is for this reason that it has four acid constants (pka ₁, pka ₂, pka ₃ and pka ₄).

Molecular dynamism

The alkyl chain is capable of rotating its single bonds, conferring flexibility and dynamism to the molecule. The amino group can do the same to a lesser degree. However, phosphate groups can only rotate the P ─ C bond (like two rotating pyramids).

On the other hand, these “rotating pyramids” are hydrogen bond acceptors and, when they interact with another species or molecular surface that provides these hydrogens, they slow down and cause alendronic acid to anchor tenaciously. Electrostatic interactions (caused, for example, by Ca ²⁺ ions) also have this effect.

Meanwhile, the rest of the T continues to move. The amino group, still free, interacts with the environment that surrounds it.

Properties

Alendronic acid is a white solid that melts at 234ºC and then decomposes at 235ºC.

It is very poorly soluble in water (1mg / L) and has a molecular weight of approximately 149 g / mol. This solubility increases if it is in its ionic form, alendronate.

It is a compound with a great hydrophilic character, so it is insoluble in organic solvents.

Applications

It has applications in the pharmaceutical industry. It is commercially available under the names Binosto (70 mg, effervescent tablets) and Fosamax (10 mg tablets and 70 mg tablets administered once a week).

As a non-hormonal drug, it helps fight osteoporosis in menopausal women. In men it acts on Paget's disease, hypocalcemia, breast cancer, prostate cancer and other diseases associated with the bones. This reduces the risk of possible fractures, especially of the hips, wrists, and spine.

Its high selectivity towards the bones allows the consumption of its doses to be reduced. For this reason, patients hardly need to consume a tablet weekly.

Mechanism of action

Alendronic acid is anchored to the surface of the hydroxyapatite crystals that make up bone. The ─ OH group of bisphosphonic carbon favors interactions between acid and calcium. This occurs preferentially in bone remodeling conditions.

As the bones are not inert and static structures but dynamic, this anchoring exerts an effect on the osteoclast cells. These cells carry out the resorption of the bone, while the osteoblasts are in charge of building it.

Once the acid is anchored to the hydroxyapatite, the upper part of its structure - specifically the -NH _2- group _- inhibits the activity of the enzyme farnesyl pyrophosphate synthetase.

This enzyme regulates the synthetic mevalonic acid pathway and therefore directly affects the biosynthesis of cholesterol, other sterols, and isoprenoid lipids.

As lipid biosynthesis is altered, protein prenylation is also inhibited, therefore, without the production of essential lipid proteins for the renewal of osteoclast functions, they end up dying (osteoclast apoptosis).

As a consequence of the above, the osteoclastic activity decreases and the osteoblasts can work in the construction of the bone, strengthening it and increasing its density.

Alendronic acid derivatives

To obtain a derivative, it is essential to modify the molecular structure of the compound through a series of chemical reactions. In the case of alendronic acid, the only possible modifications are those of the -NH ₂ and -OH groups (of the bisphosphonic carbon).

What modifications? It all depends on the synthesis conditions, reagent availability, scaling, yields, and many other variables.

For example, one of the hydrogens can be replaced by a group R ─ C = O, creating new structural, chemical and physical properties in the derivatives.

However, the objective of such derivatives is none other than to obtain a compound with better pharmaceutical activity and that, in addition, shows fewer sequelae or undesirable side effects to those who consume the drug.

References

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2. Turhanen, PA, & Vepsäläinen, JJ (2006). Synthesis of novel (1-alkanoyloxy-4-alkanoylaminobutylidene) -1,1-bisphosphonic acid derivatives. Beilstein Journal of Organic Chemistry, 2, 2. doi.org
3. DrugBank. (June 13, 2005). DrugBank. Retrieved on March 31, 2018, from: drugbank.ca.
4. Marshall, H. (May 31, 2017). Alendronic acid. Retrieved on March 31, 2018, from: netdoctor.com
5. PubChem. (2018). Alendronic Acid. Retrieved on March 31, 2018, from: pubchem.ncbi.nlm.nih.gov.
6. Wikipedia. (March 28, 2018). Alendronic acid. Retrieved on March 31, 2018, from: en.wikipedia.org.