6. Drugs for GI & GORD Medicinal Chem

PHAY2004: Body Systems and Therapeutics 3 – Medicinal Chemistry of GI and GORD Drugs

Antacids Antacids are generally alkaline inorganic salts that react with excess hydrochloric acid in the stomach resulting in neutralisation. They are most commonly the carbonate (CO3

2–) salts of magnesium (Mg2+) or calcium (Ca2+), the hydrogencarbonate (HCO3

– also known as bicarbonate) salts of potassium (K+) or sodium (Na+) or the hydroxides (OH–) of magnesium or aluminium (Al3+). CaCO3 + HCl → NaHCO3 + HCl → Al(OH)3 + HCl → There are several limitations to the usefulness of antacids in the long-term management of GORD. Regular use of antacids may result in constipation or diarrhoea or discomfort due to accumulation of CO2 in the intestines. Excessive or prolonged consumption can also affect blood pH and lead to systemic absorption of unusually high quantities of metal ions. A principal issue is that antacids only help with the management of excess gastric acid; they do not reduce the acid secretion that may be the underlying cause. Some antacids, notably CaCO3, seem in fact to promote acid secretion, which may result in symptoms returning a short while later (acid rebound). Antacids also have the potential to interfere with the absorption of other drugs administered at the same time, and patients should be encouraged not to take antacids at the same time as other medicines. An increase in gastrointestinal pH may alter the ionisation state of acidic and/or basic drugs, which may affect their absorption. Antacids can also affect the integrity of enteric coatings. These coatings are designed to protect drugs from the acidic environment of the stomach, and are designed to break down at higher pH (such as the pH found in the small intestine). In addition, the metal ions found in most antacids can undergo chelation by some drugs, often resulting in the formation of poorly-soluble complexes, which may be less effectively absorbed. Histamine H2 Receptor Antagonists Histamine promotes acid secretion through activation of parietal cell H2 receptors. Although this effect of histamine was known at the time that H2 receptor antagonists were being developed, the receptor itself had not been identified, and much of the development of this class of drug was done without knowledge of their molecular target.

Histamine contains a primary amino group (pKa = 9.8), which is around 10,000 times stronger as a base than the imidazole ring (pKa = 5.7). The primary amino group is protonated and positively charged at physiological pH. It is important to remember (see PHAY1002: Chemistry of Medicines) which of the two nitrogen atoms in the imidazole ring has a lone pair and is available to accept a proton. After protonation, the conjugate acid of imidazole is stabilised by resonance:

In this way, a proton in the uncharged imidazole ring is effectively able to transfer from one nitrogen atom to the other, via the protonated intermediate. The two isomers of imidazole that interconvert in this manner are called tautomers and the process is referred to as tautomerisation. Histamine is an agonist at both H1 and H2 receptors. Histamine receptor agonists typically contain a basic amino group that is protonated at physiological pH, separated by a flexible chain from a heteroaromatic ring


(like imidazole) that contains a nitrogen atom in the position adjacent to the chain. We have already encountered H1 receptor antagonists such as diphenhydramine, chlorphenamine and cetirizine, which are used to treat allergies. These anti-histamines usually also have a basic amino group, separated by a flexible chain from an atom bonded to two aromatic rings. In contrast, H2 receptor antagonists usually contain a non-basic polar group separated by a flexible chain from a nitrogen-containing heterocycle (or a heterocycle with a nitrogen-containing substituent). The first successful H2 receptor antagonist developed was cimetidine.

Cimetidine was released in 1976 and soon became the world’s biggest-selling prescription drug (until eventually surpassed by ranitidine, another H2 antagonist). Cimetidine revolutionised ulcer treatment, effectively eliminating the reliance on poorly-effective antacids and removing the need for surgical intervention in a great many cases. Cimetidine contains an imidazole ring, separated by a thioether-containing flexible chain from a highly polar group. These are the general requirements for this class of drugs. The polar group is based upon guanidine, which is one of the most basic groups found in organic chemistry. The side chain of the amino acid arginine contains a guanidine group with a pKa (for the conjugate acid) of 12.5, making it a stronger base than most amines.

The basicity of the guanidine group is a consequence of the fact that the positive charge that results from protonation can be stabilised by resonance. The most basic nitrogen atom is the one that is doubly-bonded to the carbon atom. The other two nitrogen atoms are effectively non-basic as all of their electrons are involved in bonding and neither has a lone pair of electrons available to accept a proton. This is similar to the nitrogen atoms found in amides.

After protonation, the positive charge in the guanidinium cation is effectively spread out over all three nitrogen atoms, giving greater stability.

However, in order to bind selectively as an antagonist at H2 receptors, a polar non-basic group is required. If cimetidine contained an unmodified guanidine group in the same position, this would clearly be unsuitable. Adding a strongly electron-withdrawing group such as a cyano group (or a nitro group) greatly reduces the basicity of the guanidine. A cyanoguanidine group is found in cimetidine. The pKa of this group is 0.4, around a million million times less basic than an unmodified guanidine! The cyano group withdraws electron density from the guanidine, enormously reducing the availability of the nitrogen lone pair and effectively rendering it


unable to accept a proton and therefore non-basic. The cyanoguanidine group is still highly polar, and cimetidine’s overall polarity is fairly high (log P = 0.4, similar to that of paracetamol; water solubility is around 9.4 g L-1). As a fairly polar drug, cimetidine is cleared primarily via the kidneys and a dose reduction may be required in renal impairment. Some metabolism does take place in the liver, with oral bioavailability around 60% mainly due to first-pass metabolism. Cimetidine also has sufficient water solubility to allow its formulation as an oral solution. Several drug-drug interactions are evident with cimetidine, primarily as a consequence of its ability to act as an inhibitor of CYP450 enzymes. It inhibits the metabolism of a number of drugs including diazepam, lidocaine, warfarin, theophylline and phenytoin. This inhibition is thought to be related to the imidazole ring, and was one of the driving factors in the development of newer H2 receptor antagonists. Ranitidine was introduced in 1981 and surpassed the success of cimetidine in 1988. The drug earned £7 billion in sales over a ten-year period and was earning over £4 million per day at the height of its popularity. Ranitidine contains a tertiary amine-substituted furan ring in place of the imidazole ring of cimetidine, which reduces its potential for drug-drug interactions. The cyanoguanidine of cimetidine is also replaced by a nitroketeneaminal. This complex functional group is similar to a guanidine group in which the doubly-bonded nitrogen atom is replaced by a carbon atom. The nitro substituent carries out the same electron-withdrawing function as the cyano group in cimetidine. Ranitidine is classified as a General Sales List medicine.

Other H2 receptor antagonists include famotidine (introduced in 1985) and nizatidine (introduced in 1987). Both are structurally related to cimetidine and ranitidine, each containing a thiazole ring as their heterocycle component. Nizatidine is otherwise identical to ranitidine, but famotidine has a guanidine substituent attached to the thiazole ring and its polar group is made up of an amidine with an electron-withdrawing sulfonamide (–SO2NH2).

While H2 receptor antagonists revolutionised ulcer and GORD treatment, the action of histamine on H2 receptors is only one of several ways in which acid secretion can be promoted. It would be far more effective clinically to target the actual step by which gastric acid is secreted into the stomach from the parietal cells. This can be achieved by inhibiting the H+/K+ ATPase (the proton pump) itself. Proton Pump Inhibitors (PPIs) Proton pump inhibitors (H+/K+ ATPase inhibitors) act by covalently modifying the amino acid sequence of the proton pump, resulting in its inactivation. The first such agent developed was omeprazole, which was originally developed as an anti-viral drug. After its launch in 1988, it went on to become the best-selling drug ever by 1996 and made £3.6 billion profit in 2000.


Omeprazole contains two basic heterocyclic functional groups – a benzimidazole (imidazole fused to benzene) ring system and a pyridine ring. Of these two, it is the benzimidazole (pKa = 8.7 for the conjugate acid) ring that is the more basic (pKa = 4.0 for the pyridine nitrogen) as the positive charge produced on protonation is more stable. This difference in basicity is key to how the drug works. In the highly acidic environment near the parietal cell, a greater proportion of the benzimidazole will be protonated and positively charged than the pyridine. This protonation is the first step in the chemical rearrangement of omeprazole, which results in its conversion to a highly reactive sulfenamide intermediate (omeprazole is a pro-drug). You will NOT be expected to remember the details of the reaction mechanism involved.

The sulfenamide product of the rearrangement above is highly reactive towards thiol (–SH) groups such as those found in the side chains of cysteine residues. The proton pump protein sequence is very rich in cysteine amino acids. The sulfenamide product from omeprazole targets Cys813 (and Cys892) in the proton pump sequence forming a disulfide bond (Cys321 and Cys822 are also targeted by other PPIs). This covalent modification prevents the pump from carrying out its normal function.

While PPIs take some time to reach full therapeutic effectiveness, they can eventually result in the inactivation of up to 70% of pumps. In general, pump function can only be reliably restored by the synthesis of new pumps, but there is evidence to suggest that some disulfides can be reduced to regenerate the original cysteine residues and restore activity. In order to reach its site of action, omeprazole must first be absorbed into systemic circulation (it cannot reach the proton pumps directly from the contents of the stomach). Due to its instability in acidic conditions, omeprazole must be administered in an enteric coated formulation, otherwise the rearrangement would occur in the contents of the stomach and the sulfenamide would react with any available thiol groups (such as on food). The enteric coated formulations pass through intact to the small intestine where the higher pH causes release of the drug allowing effective absorption. Dispersible tablets made from enteric coated pellets (MUPS® = multiple unit pellet system) are available and can be dispersed in a suitable liquid for oral administration. The pH of the dispersion liquid cannot be too high or it will cause premature release of the drug. The recommendation is to disperse in water or fruit juice and swallow immediately; carbonated water and milk should not be used. The pellets should not be chewed or crushed. While it may not be immediately obvious from looking at the structure, omeprazole is a chiral molecule. The sulfur atom that is present in the sulfoxide is actually tetrahedral. Sulfur has six valence electrons. In the structure as drawn, two electrons are shared with oxygen in the double bond, one with the carbon on the left

N

HN

S

O

H

O

N

O

NH

HN

S

O

O

N

O

NH

HN

O

S

N

O

O

H

NH

N

O

N O

SHO

H

H

NH

N

O

N O

SH2O

NH

N

O

N O

S

NH

N

O

N O

S

H+/K+ ATPaseS H

NH

N

O

N O

S

H+/K+ ATPaseS


and one with the carbon on the right. This means that there are two unshared electrons remaining and so the sulfur atom has a lone pair of electrons. If we draw the structure of dimethylsulfoxide (DMSO), you can see that two resonance contributors are possible, just as we saw in PHAY1002 with the carbonyl group.

We can think of the sulfoxide as most resembling the right-hand resonance contributor above, in which it has eight electrons in its valence shell. These eight electrons are in four pairs – two bonds with carbon, one bond with oxygen and one lone pair. These four pairs will get as far away from each other as possible and adopt a tetrahedral arrangement, very similar to that of an amine (or ammonia). If the two carbon substituents are different (as they are in omeprazole), then the sulfur has four different groups attached and thus is chiral with two mirror image enantiomers possible.

Omeprazole is manufactured and administered as a racemic mixture of enantiomers. It is common to find both types of structural representation (S=O and +S–O–) used for omeprazole as were used for the resonance forms of DMSO above.

The pure (S) enantiomer of omeprazole, esomeprazole, has been successfully marketed as Nexium®. Both enantiomers undergo the same chemical rearrangement to generate the same sulfenamide intermediate, and so we can consider the two enantiomers, unusually, to have equal activity. There is evidence, however, that esomeprazole may be slightly more effective on a dose-for-dose basis as it has slightly higher bioavailability, primarily due to its slower metabolism. As metabolism is a consequence of interaction with enzymes (which have highly specific active sites), we expect the enantiomers to be metabolised differently. There is also limited evidence to suggest that there may be less inter-patient variability and a lower potential for drug-drug interactions with esomeprazole due to these differences in metabolism. The other PPIs in current clinical use in the UK are lansoprazole, pantoprazole and rabeprazole. They differ from omeprazole only in the substituents on the benzimidazole and/or pyridine rings and they all undergo the same type of acid-catalysed rearrangement to sulfenamide derivatives that covalently modify cysteine residues on the proton pump. A single enantiomer form of lansoprazole (dexlansoprazole, Dexilant®) is also available in the USA and an additional PPI, tenatoprazole, with a prolonged duration of action, is in clinical development.

One other drug that also acts on the proton pump and which is also still in clinical trials (currently approved for use only in Korea) is revaprazan. This is the prototypical member of a new class of drugs called

SO

N

R1

R2


potassium-competitive acid blockers (P-CABs). Revaprazan binds competitively to a site near the K+ ion channel of the proton pump, inhibiting its action

Anti-motility Agents Loperamide (present in Imodium®) is an opioid drug used in the management of diarrhoea. Loperamide acts on the -opioid receptors present on the myenteric plexus causing reduced smooth muscle tone and decreased contraction activity in the intestinal walls. It shares this activity with other classical -agonists (like morphine), which often have constipation as a side-effect. Agonism at -opioid receptors in the CNS is also associated with analgesia, respiratory depression, dependence, euphoria and nausea. Structurally, loperamide has similar features to other opioid drugs like methadone and pethidine.

Loperamide contains a basic tertiary amino group that has a pKa of 8.6 (conjugate acid) and so is predominantly protonated and positively charged at physiological pH. This is a feature common to the majority of opioid drugs. The tertiary amide nitrogen is non-basic. Loperamide has quite low overall polarity in the unionised form. There is sufficient unionised drug (around 6%) present at physiological pH for it to be readily able to diffuse across membranes such as the blood-brain barrier (despite it often being stated that this is not the case). However, once in the CNS, the drug is actively and rapidly pumped back out into the blood by the efflux transporter P-glycoprotein. Consequently levels of loperamide in the CNS are extremely low, which limits its ability to cause unwanted central effects. Some drugs, notably quinidine, act as inhibitors of P-glycoprotein and can lead to accumulation of loperamide in the CNS, along with the associated undesirable side-effects. While there remains a theoretical risk of loperamide accumulation with other inhibitors (including omeprazole and piperine from black pepper), the clinical significance of these interactions seems limited.

6. Drugs for GI & GORD Medicinal Chem

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