1976: Cimetidine: First H2-Receptor Antagonist (1976)

Peptic ulcer disease was among the most common chronic conditions in the 20th century, causing
significant morbidity and a mortality rate from complications (perforation, haemorrhage) of
5–10%. Available treatments—antacids, milk diets, anticholinergics—provided modest symptomatic
relief but did not reliably heal ulcers or prevent recurrence. Elective surgery (vagotomy) was
often required for severe cases.

James Black, fresh from his success with propranolol at ICI, joined Smith Kline & French
Laboratories and applied the same receptor-based rational design approach to gastric acid secretion.
Histamine was known to stimulate gastric acid via a receptor that was not the classical H1 receptor
(the target of antihistamines). Black and colleagues, including C. Robin Ganellin and Graham Durant,
systematically modified the histamine molecule to achieve selectivity for the gastric H2 receptor.
After seven years of medicinal chemistry work and approximately 700 compounds tested, metiamide
and then cimetidine emerged as selective H2-receptor antagonists.

Cimetidine was approved by the FDA in August 1976 and launched as Tagamet. It rapidly became the
world's first billion-dollar drug—demonstrating that blockbuster pharmaceutical revenues were
achievable—and transformed the management of peptic ulcer disease. Ulcer healing rates with
cimetidine were 75–90% at 4 weeks, far exceeding anything previously available without surgery.

The H2-blocker class was subsequently improved by ranitidine (1981), famotidine (1986), and
nizatidine, but all were eventually supplanted for most indications by proton pump inhibitors
(PPIs), beginning with omeprazole (1992), which achieved more profound and sustained acid
suppression by directly blocking H+/K+-ATPase.