Discovery, synthesis, and structure-activity relations of 3,4-dihydro-1 H -spiro(naphthalene-2,2′-piperidin)-1-ones as potassium-competitive acid blockers

Autor: Yasunobu Hori, Akio Imanishi, Naoki Tarui, Yasushi Fujioka, Toshihiro Imaeda, Fumio Itoh, Mitsuyo Kondo, Haruyuki Nishida, Koji Ono, Masahiro Kajino, Kazuo Nakai, Nobuhiro Inatomi, Jun Matsukawa, Terufumi Takagi
Rok vydání: 2017
Předmět:
0301 basic medicine
Drug
Stereochemistry
Potassium
media_common.quotation_subject
Clinical Biochemistry
Drug Evaluation
Preclinical
Pharmaceutical Science
chemistry.chemical_element
Naphthalenes
Inhibitory postsynaptic potential
Biochemistry
Gastric Acid
H(+)-K(+)-Exchanging ATPase
Inhibitory Concentration 50
Structure-Activity Relationship
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Piperidines
Drug Discovery
medicine
Animals
Spiro Compounds
Secretion
Molecular Biology
media_common
Naphthalene
Binding Sites
Stomach
Organic Chemistry
Proton Pump Inhibitors
Rats
Molecular Docking Simulation
030104 developmental biology
medicine.anatomical_structure
ROC Curve
chemistry
Gastric Mucosa
Docking (molecular)
Area Under Curve
030220 oncology & carcinogenesis
Molecular Medicine
Gastric acid
Administration
Intravenous
Half-Life
Histamine
Zdroj: Bioorganic & Medicinal Chemistry. 25:3719-3735
ISSN: 0968-0896
DOI: 10.1016/j.bmc.2017.05.012
Popis: With the aim to discover a gastric antisecretory agent more potent than the existing proton pump inhibitors, novel 3,4-dihydro-1H-spiro(naphthalene-2,2'-piperidin)-1-one derivatives, which could occupy two important lipophilic pockets (described as LP-1 and LP-2) of H+,K+-ATPase and can strongly bind to the K+-binding site, were designed based on a docking model. Among the compounds synthesized, compound 4d showed a strong H+,K+-ATPase-inhibitory activity and a high stomach concentration in rats, resulting in potent inhibitory action on histamine-stimulated gastric acid secretion in rats. Furthermore, 4d exerted significant inhibitory action on histamine-stimulated gastric-acid secretion in rats with a rapid onset and moderate duration of action after the administration. These findings may lead to a new insight into the drug design of potassium-competitive acid blockers.
Databáze: OpenAIRE
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