Structure–Activity Characterization of an H2-Receptor Antagonist, 3-Amino-4-[4-[4-(1-piperidinomethyl)-2-pyridyloxy]-cis-2-butenylamino]-3-cyclobutene-1,2-dione Hydrochloride (IT-066), Involved in the Insurmountable Antagonism against Histamine-Induced Positive Chronotropic Action in Guinea Pig Atria

Q2 · MEDICINE

Article

Author: Haruko Kijima ; Masaji Suzuki ; Makoto Muramatsu ; Yoshihiko Isobe ; Shohei Higuchi ; Sadakazu Yokomori

IT-066 (3-amino-4-[4-[4-(1-piperidinomethyl)-2-pyridyloxy]-cis-2- butenylamino]-3-cyclobutene-1,2-dione hydrochloride), an H2-receptor antagonist, shows highly potent, time-dependent, and irreversible antagonism at H2-receptors. We identified the structurally important parts of IT-066 involved in its interaction with the H2-receptor, and explored its unique mode of action by investigating the H2-receptor blocking action of IT-066 and related compounds in guinea pig isolated atria. IT-066 is structurally divided into three different parts: a tertiary amine and hydrophobic group, a connecting carbon chain, and a polar group. Though the replacement of its pyridine ring with a benzene ring maintained the mode of the H2-receptor blocking action of IT-066, the oxidation of the piperidine ring completely attenuated this blocking action. By replacing the connecting carbon chain of IT-066, cis-2-butene, with butane, trans-2-butene, or 2-butyne, the irreversible antagonism disappeared and the potency was reduced. On the other hand, BMY25368, whose connecting carbon chain is trimethylene, showed irreversible antagonism comparable to that of IT-066. Hydrolysis of the polar group of IT-066 completely attenuated the H2-receptor blocking activity. Among the compounds tested, only the compound that had 3,4-diamino-3-cyclobutene-1,2-dione as a polar group showed time-dependent and insurmountable H2-receptor blocking action. These data suggest the importance of the following structural features of IT-066: the piperidine ring of IT-066 and -NH2 in its polar group are essential for the interaction with the H2-receptor; and the 3,4-diamino-3-cyclobutene-1,2-dione group and the connecting carbon chain of IT-066 are crucial for determining the irreversibility of H2-receptor blocking action, though the connecting carbon chain is replaceable with another chain with appropriate length and configuration.

01 Jan 1991·Scandinavian Journal of GastroenterologyQ4 · MEDICINE

Is the Time of Dosing of a Potent Long-Acting H₂-Receptor Antagonist Critical? Twenty-Four-Hour pH Measurements with SKF-94482

Q4 · MEDICINE

Article

Author: Wilder-Smith, C H ; Merki, H S

Reduction of daytime as well as nighttime acidity is important in the healing of duodenal ulceration and reflux oesophagitis. The importance of the time of dosing of potent, long-acting H2 blockers for optimal suppression of intragastric acidity is unknown. The efficacy of different oral dosage regimens of SKF-94482, a new, competitive and long-acting H2-receptor antagonist, in reducing daytime and nighttime intragastric acidity was studied with 24-h pH-monitoring in 3 double-blind, randomized, crossover trials in 45 fed, healthy subjects. In study A 200 mg, 400 mg, or 600 mg SKF-94482 or placebo was given at 0830 h for 6 days. In study B the above doses were taken at 1830 h. In study C 200 mg or 300 mg of SKF-94482 or placebo was given at 0830 and 1830 h for 6 days. SKF-94482, 400 mg, was the most effective dose, and twice daily dosing was of no additional pharmacodynamic benefit. When 400 mg SKF-94482 was given at 0830 h, the median 24-h, day (0800-1800 h) and night (1800-0800 h) pH (interquartile range) were 2.6 (2.2-3.2), 2.3 (2.1-3.8), and 2.6 (1.8-3.6), respectively. When the time of dosing was 1830 h with 400 mg SKF-94482, median 24-h, day and night pH were 3.4 (2.5-4.0), 3.4 (3.1-4.3), and 3.7 (2.8-5.9), respectively. Early-evening dosing of this long-acting H2 antagonist resulted in substantially greater suppression of intragastric acidity than morning dosing.

01 Jan 1991·American journal of veterinary research

Effects of a histamine type-2 receptor antagonist (BMY-25368) on gastric secretion in horses.

Article

Author: Dreyfuss, D J ; Spencer, P A ; Uhlman, R ; Vecchione, J ; Orsini, J A

The effects of a potent new histamine-2 (H2) receptor antagonist, BMY-25368, were studied on gastric acid secretion in 5 foals from which food was withheld. Doses of 0.02, 0.11, 0.22, and 1.10 mg/kg of body weight were administered IM in a randomly assigned treatment sequence. Following BMY-25368 administration, hydrogen ion concentration was decreased and mean pH was higher than baseline values in a dose-response pattern. At the 0.22 and 1.10 mg/kg doses, the high pH was sustained for greater than 4 hours. The BMY-25368 thus may be useful for treating gastric ulcer disease in horses.

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Indication	Highest Phase	Country/Location	Organization	Date
Stomach Ulcer	Phase 3	US	Bristol Myers Squibb Co.	-

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