Discovery and development of bisphosphonates

<h2 id="discovery">Discovery</h2>
Bisphosphonates were originally synthesized in the 19th century and used in industry for their <a href="/facts/Water_softening/66wnC1ml">antiscaling</a> and anticorrosive properties. In the late 1960s their potential to treat diseases related to the metabolism of the bones became evident. The first generation of bisphosphonates included <a href="/facts/Etidronic_acid/zdQzMnko">etidronic acid</a> and <a href="/facts/Clodronic_acid/E66kVTI6">clodronic acid</a> which were introduced in the 1970s and 1980s. They were the first bisphosphonate drugs to be used successfully in the clinic.<a class="footnote-ref" id="fnref:1" href="#fn:1">1</a> They have since then been developed further with the intention to make them more potent, enhance their distribution inside the bone and extend the duration of action. This has made it possible to give <a href="/facts/Zoledronic_acid/g3oMtI5Q">zoledronate</a>, the most recent bisphosphonate drug to be placed on the market, in a single annual dose by intravenous infusion.<a class="footnote-ref" id="fnref:2" href="#fn:2">2</a>

<h2 id="development">Development</h2>
The original bisphosphonates (first generation) were simple molecules with small groups of single atoms or <a href="/facts/Alkyl/vmEk8X4v">alkyl</a> chains in position R1 and R2. They only had a rather weak inhibiting effect on bone resorption. The inclusion of an amino group marked the beginning of the second generation of bisphosphonates with higher potency. The first was <a href="/facts/Pamidronate/coSgPbh8">pamidronate</a> and similar analogues followed where the position of the nitrogen in the side chain was the key to a more potent drug. Later it became apparent that the nitrogen does not necessarily have to be connected to an alkyl chain but instead using a <a href="/facts/Heterocyclic_compound/8oYSjJxY">heterocyclic</a> group. A few such drugs have been developed and placed on the market where zoledronate is the most notable one. <a href="/facts/Minodronic_acid/EDlrClPK">Minodronic acid</a> is even more potent and has been placed on the market in Japan. Their potency is such that it is effective even in picomolar concentration.<a class="footnote-ref" id="fnref:3" href="#fn:3">3</a>
Further development has not resulted in the placing on the market of compounds in equal potency. Arylalkyl substitutes of pamidronate are among the most recent bisphosphonates to be used clinically where the hydroxyl group in position R2 has been omitted to ensure stability.<a class="footnote-ref" id="fnref:4" href="#fn:4">4</a>
Recent research in this area has opened up an opportunity to develop new bisphosphonate drug therapies.
Bisphosphonates with a more <a href="/facts/Lipophilicity/AWpsR8Xe">lipophilic</a> character have been developed and have shown potential as a tumor suppressant. They operate by a slightly different mechanism in which they not only inhibit the key enzyme farnesyl pyrophosphate synthase (FPPS) of the <a href="/facts/Mevalonate_pathway/uHea16r2">mevalonate pathway</a> but also geranylgeranyl pyrophosphate synthase (GGPS), an enzyme also located in the mevalonate pathway. They do not have the same affinity for the <a href="/facts/Bone_mineral/L6LpbEYE">bone minerals</a>.<a class="footnote-ref" id="fnref:5" href="#fn:5">5</a>
GGPS has since been successfully inhibited by a novel bisphosphonate compound with a <a href="/facts/Triazole/nyYdyRW4">triazole</a> group within R2 and a methyl group in R1. This may become useful in therapies against <a href="/facts/Malignancies/PVW6n1D0">malignancies</a> like multiple myeloma.<a class="footnote-ref" id="fnref:6" href="#fn:6">6</a>
In 2018, a <a href="/facts/Dendrimer/3aXUKBej">dendritic</a> bisphosphonate was introduced containing three bisphosphonate units. It has shown potential for bone specific delivery of large therapeutic molecules by taking advantage of the high affinity of bisphosphonates to the bone minerals <a class="footnote-ref" id="fnref:7" href="#fn:7">7</a>

<h2 id="mechanism-of-action">Mechanism of action</h2>

The <a href="/facts/Mechanism_of_action/Sjk8vfV4">mechanism of action</a> of the bisphosphonates (BP's) has evolved as new generations of drugs have been developed. The function of the first generation bisphosphonates differs from the more recent <a href="/facts/Nitrogen/Nf1QpGDz">nitrogen</a> containing BP's but both are apparently internalised by <a href="/facts/Endocytosis/NJjChLNj">endocytosis</a> of a membrane-bound vesicle where the drug is most likely in a <a href="/facts/Complex_(chemistry)/1tCyeQUm">complex</a> with <a href="/facts/Ca%25C2%25B2%25E2%2581%25BA/wgUxKej5">Ca2+ ions</a>. This does not concern other cells in the bone as this takes place by a selective uptake of osteoclasts.<a class="footnote-ref" id="fnref:8" href="#fn:8">8</a>
The common function which applies to all bisphosphonate drugs is a physicochemical interaction with the bone mineral to prevent the physical resorption of the bone by the <a href="/facts/Osteoclasts/jHHtEQru">osteoclasts</a>. This is especially relevant at sites where <a href="/facts/Bone_remodeling/eoanghIb">bone remodelling</a> is most active.<a class="footnote-ref" id="fnref:9" href="#fn:9">9</a><a class="footnote-ref" id="fnref:10" href="#fn:10">10</a> The bisphosphonates have an intrinsic affinity for the calcium ions (<a href="/facts/Hydroxyapatite/SqcXuXVQ">hydroxyapatite</a>) of the bone mineral just as the endogenous <a href="/facts/Pyrophosphate/L9FPEkhF">pyrophosphates</a>. The difference lies in the non-hydrolysable carbon-phosphorus bond of the bisphosphonates which prevents their metabolism and at the same time ensure an effective <a href="/facts/Absorption_(pharmacology)/LCezQPJK">absorption</a> from the <a href="/facts/Gastrointestinal_tract/nK2zwqBS">gastrointestinal tract</a>.<a class="footnote-ref" id="fnref:11" href="#fn:11">11</a>
The primary inhibiting action of the first generation of bisphosphonates on osteoclasts is by inducing <a href="/facts/Apoptosis/8dVzSm4y">apoptosis</a>. The mechanism of action is apparently by the formation of an ATP analogue or metabolite of the bisphosphonates like etidronic acid and clodronic acid. The ATP analogue accumulates in the <a href="/facts/Cytosol/VyXgygWm">cytosol</a> of the osteoclast with a cytotoxic effect.<a class="footnote-ref" id="fnref:12" href="#fn:12">12</a>
The primary mechanism of action of the more developed nitrogen containing bisphosphonates is however by cellular effects on osteoclasts through inhibition of the mevalonate pathway and in particular the subsequent formation of <a href="/facts/Isoprenoid/1GvG7W7v">isoprenoid</a> lipids. The inhibition takes place at a key branch point in the pathway catalyzed by farnesyl pyrophosphate synthase (FPPS).<a class="footnote-ref" id="fnref:13" href="#fn:13">13</a> Isoprenoid lipids are necessary for <a href="/facts/Post-translational_modification/KMUayTIc">post-translational modifications</a> of small GTP-binding regulatory proteins like Rac, Rho and Ras of the <a href="/facts/Ras_superfamily/2DsdANGx">Ras superfamily</a>. The function of osteoclasts depends on them for a variety of cellular processes like apoptosis.<a class="footnote-ref" id="fnref:14" href="#fn:14">14</a>

<h2 id="structure-activity-relationship">Structure activity relationship</h2>

<h3>Pharmacophore</h3>
Bisphosphonates mimic the <a href="/facts/Endogeny_(biology)/DFkSLkRI">endogenous</a> <a href="/facts/Inorganic_compound/TfFfzxSz">inorganic</a> <a href="/facts/Pyrophosphate/L9FPEkhF">pyrophosphate</a> where the <a href="/facts/Oxygen/acyn6o8r">oxygen</a> backbone is replaced with <a href="/facts/Carbon/ukrgQexo">carbon</a> (P-C-P for P-O-P). The two additional groups or <a href="/facts/Side_chain/Lw8KPAXn">side chains</a> on the carbon backbone are usually referred to as R1 and R2. R1 is usually a <a href="/facts/Hydroxy_group/1Hs2QAEv">hydroxyl</a> group which enhances the affinity for the <a href="/facts/Calcium/hf252CC0">calcium</a> by forming a <a href="/facts/Tridentate_ligand/xdrkcRGB">tridentate ligand</a> along with the phosphate groups. The compound can be made more potent by optimizing the <a href="/facts/Chemical_structure/r5rT1Lj4">structure</a> of the R2 group to best inhibit <a href="/facts/Bone_resorption/cMx23mGW">bone resorption</a>.<a class="footnote-ref" id="fnref:15" href="#fn:15">15</a>

<h3>Phosphonate</h3>
<a href="/facts/Phosphonate/8mg6nNRP">Phosphonate</a> groups in the chemical structure are important for the binding of the drug to the target enzyme. Studies have shown that removal or replacement of the phosphonate group with a <a href="/facts/Carboxylic_acid/U4xuMosy">carboxylic acid</a> causes drastic loss in potency of the drug and the <a href="/facts/Enzyme_inhibitor/MkFwGXHJ">enzyme inhibitor</a> no longer goes into an <a href="/facts/Isomerized/PXlvDVdg">isomerized state</a>.<a class="footnote-ref" id="fnref:16" href="#fn:16">16</a>

<h3>Hydroxyl group (R1 side chain)</h3>
Modification of the R1 side chain on bisphosphonates is very minor today, single hydroxyl group at that position seems to give the best results in terms of activity. The hydroxyl group plays a role in forming a water-induced bond with <a href="/facts/Glutamine/t94zX4SK">glutamine</a> (Gln240) on the target enzyme. Drugs that have no hydroxyl group initially cause better inhibition than parent compounds, without hydroxyl group the drug seems to fit more easily into the open <a href="/facts/Active_site/u9ua7rGu">active site</a>. The absence of hydroxyl group however reduces the ability to hold the target enzyme complex in isomerized state. <a href="/facts/Biological_activity/jJ14jyvc">Biological activity</a> of bisphosphonates with hydroxyl group, therefore, appears over longer time.<a class="footnote-ref" id="fnref:17" href="#fn:17">17</a>

<h3>Nitrogen (R2 side chain)</h3>
<a href="/facts/Nitrogen/Nf1QpGDz">Nitrogen</a> containing bisphosphonates are the current most used drugs in the class because of their <a href="/facts/Potency_(pharmacology)/D38FDyPh">potency</a>.<a class="footnote-ref" id="fnref:18" href="#fn:18">18</a> Studies have shown that nitrogen on bisphosphonates forms <a href="/facts/Hydrogen_bond/85V86IIg">hydrogen bond</a> with <a href="/facts/Threonine/7zffFQ6W">threonine</a> (Thr201) and the <a href="/facts/Carbonyl_group/KJ71bo3X">carbonyl</a> part of <a href="/facts/Lysine/CEetgA9L">Lysine</a> (Lys200) on target enzyme, therefore enhancing the binding of the complex. Altering the position of nitrogen can significantly change the ability for the nitrogen hydrogen bond to occur.<a class="footnote-ref" id="fnref:19" href="#fn:19">19</a>

Relative potency of nitrogen containing bisphosphonates<a class="footnote-ref" id="fnref:20" href="#fn:20">20</a><table><tbody><tr><th>Bisphosphonate</th><th>potency (relative)</th></tr><tr><td>Alendronate</td><td>1-5</td></tr><tr><td>Risedronate</td><td>10</td></tr><tr><td>Zoledronate (IV)</td><td>50</td></tr></tbody></table>
<h3>Modification of nitrogen containing side chain (R2 side chain)</h3>
Increased carbon length of the nitrogen R2 side chain alters activity. Side chain that is made out of three <a href="/facts/Carbon/ukrgQexo">carbons</a> has proven to be the most ideal length in terms of activity, increasing or decreasing the length of the chain from there has negative effect on biological activity. <a href="/facts/Alendronic_acid/Svu22Nmn">Alendronate</a>, a common bisphosphonate drug, has a three carbon length side chain for example.<a class="footnote-ref" id="fnref:21" href="#fn:21">21</a> <a href="/facts/Risedronic_acid/skgL4SNh">Risedronate</a> has heterocyclic structure containing nitrogen. <a href="/facts/Heterocyclic_compound/8oYSjJxY">Heterocyclic</a> nitrogen containing bisphosphonates have revealed better results in terms of activity compared to earlier bisphosphonates with nitrogen bound to carbon chain. Studies on risedronate analogous with different placement of nitrogen on the ring have shown no measurable difference on biological activity. Increased length of carbon chain connected to the ring revealed negative results.<a class="footnote-ref" id="fnref:22" href="#fn:22">22</a> <a href="/facts/Zoledronic_acid/g3oMtI5Q">Zoledronate</a> is the most potent bisphosphonate drug today only available as <a href="/facts/Intravenous_therapy/AwwuD3Nu">intravenous injection</a>. It is the only bisphosphonate drug that has two nitrogen groups in the side chain hence its potency and <a href="/facts/Route_of_administration/LsyoHTzH">route of administration</a> differs from other drugs in the same class.<a class="footnote-ref" id="fnref:23" href="#fn:23">23</a>

<h2 id="references">References</h2>

<ol>
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</ol>

Discovery and development of bisphosphonates open-in-new

Discovery and development of bisphosphonates