Figure 3.5. Representative H2-receptor antagonists to illustrate SAE.


Figure 3.5. Representative H2-receptor antagonists to illustrate SAE.

nis the preferred bioactive isomer (85,861. This prompted the preparation of many analogs in which either substituents such as chloro (87) and methylthio (88) were introduced or where the imidazole ring was re-| placed by other heterocycles.

Although 2-pyridine, 2-thiazole, and 3-iso-| thiazole were all successfully used for this purpose, the most marked increase in potency I; with respect to cimetidine was achieved by replacing the imidazole ring by a guanidinethi-azole group, to obtain tiotidine (89), as well as famotidine (90), in which the cyanoguanidine ! group had additionally been replaced by the more hydrophilic sulfamoylamidine substitu-| ent. Moreover, with greater basicity now re! siding in the exocyclic substituent than that in | the heterocyclic ring itself, the importance of this characteristic in the latter substituent diI minished. The presence of a furan ring as the heterocyclic component in ranitidine is consistent with this view (91), and a similar structural motif is also present in nizatidine (92). The dimethylaminomethyl-substituted furan of ranitidine evolved further to include piper-idinylmethyl-substituted phenyl ethers, represented by roxatidine (93). An acetyl acet-amide group was used as the hydrogen-bonding substituent in this case and higher | affinity was achieved when this group was replaced by the bulkier and more lipophilic ami-I nobenzothiazole ring, as in zolantidine (94). A similar trend toward higher affinity arising from such groups is observed in oxmetidine (95) and lupitidine (96), which can be considered to be more potent analogs of cimetidine and ranitidine, respectively.

In general, the introduction of branching to the linking chain afforded less potent compounds, whereas replacement by an aromatic linker was successful in the case of tiotidine analogs but only when the attached groups had a meta disposition (89). The thioether link has been retained in most H2 antagonists because substitution of the sulfur atom by other heteroatoms or by methylene has been detrimental to affinity at the receptor. This has been attributed to a requirement to maintain an intramolecular hydrogen bond, between the polar termini, observed in crystal structures (97) and during infrared studies (98) of H2 antagonists and which the thioether link uniquely helps to maintain. However, whether this is a necessary requirement for biological activity remains unclear.

8.2.4 Clinical Studies with H2-Receptor Antagonists. HA Hz-receptor antagonists are potent and selective inhibitors of gastric acid secretion, with numerous clinical studies to support their effectiveness in ulcer disease. Table 3.4 outlines the clinical effectiveness and pharmacokinetic profile of Hz-receptor antagonists currently available in the UK.

Cimetidine, ranitidine, famotidine, and nizatidine exhibit similar profiles of absorption, distribution, and elimination. Each of the Hz-receptor antagonists exhibits classical competitive drug-receptor interactions, with Schild slope parameters not significantly different from unity (99). The affinity of each of these drugs for the Hz-receptor is reflected in their effectivenessin inhibiting gastric acid secretion (100). Famotidine is the most potent H2-R antagonist, being 20-50 times more potent than cimetidine and 6-10 times more potent than ranitidine (101) and nizatidine. Each of these drugs is rapidly absorbed after oral administration, with peak plasma concentrations being achieved within 3 h of dosing. Oral bioavailability for these drugs ranges from 43% to 90%. With the exception of nizatidine, the bioavailability of Hz-receptor antagonists is reduced because of extensive firstpass hepatic metabolism. Only minimum plasma protein binding occurs (^30%) and all of the Hz-antagonists are eliminated quite rapidly, with a terminal half-life of 1to 3 h and a total body clearance of 24-48 L/h. Elimination is mainly attributable to renal excretion, with renal clearances ranging from 13.8 to 30 L/h. Given that the values for renal clearance greatly exceed the glomerular filtration rate (6-7.2 L/h), it is apparent that renal tubular secretion plays an important role in this process (102).

8.2.5 Adverse Effects of H2-Receptor Antagonists. The Hz-receptor antagonists are generally extremely safe drugs, with few adverse effects being reported. Cimetidine was shown to possess antiandrogen properties in a small number of patients; however, this effect

Table 3.4 An Overview of the Clinically Marketed H2-R Antagonists: Affinity, Clinical Pharmacology, and Pharmacokinetic Profile3


In vitro

Cimetidine 6.1 (193)

Famotidine 7.8(193)

Ranitidine 6.7 (193)


Clinical Pharmacology: Effect on Gastric Acid Secretion


IC50 = 2 /¿mol LT3 stimulant; pentagastrin, 40 ¡ig kg""1 h"1 (195) IC50 = 4.3 ,ug kg xh 1 stimulant pentagastrin, 0.1 /xg kg-1 ÎT1 (196)

Ranitidine (150 mg) more potent than Cimetidine (200 mg) (200)

5 mg; 40% inhibition

5 mg = inhibition to cimetidine (300 mg) (197)

30 mg 57%; 100 mg 73%; 300 mg 90%; 75 mg = . inhibition to cimetidine (300 mg) (205)

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