The activities of various types antiulcer agents against Helicobacter pylori (formerly called Campylobacter pylori) strains were determined by an agar dilution method. Among the compounds tested, two benzimidazole proton pump inhibitors, lansoprazole (AG-1749) and omeprazole, found to have significant this organism. activity was comparable that bismuth citrate, with MICs ranging from 3.13 12.5 micrograms/ml, fourfold more potent than omeprazole. A major metabolite acid-converted...

The design, synthesis, and biological activity of benzimidazole-7-carboxylic acids bearing 5-oxo-1,2,4-oxadiazole, 5-oxo-1,2,4-thiadiazole, 5-thioxo-1,2,4-oxadiazole, 2-oxo-1,2,3,5-oxathiadiazole rings are described. These compounds were efficiently prepared from the key intermediates, amidoximes 4. synthesized evaluated for in vitro vivo angiotensin II (AII) receptor antagonistic activities. Most found to have high affinity AT1 (IC50 value, 10-6−10-7M) inhibit AII-induced pressor response...

The angiotensin II (AII) antagonistic action of 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-1H-benzi mid azole-7 - carboxylic acid (CV-11974) was examined in vitro assay systems, including AII receptor binding using membrane fractions bovine adrenal cortex or rabbit aorta and AII-induced contraction aortic strips, CV-11974 its prodrug, (+/-)1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H- benzimidazole-7-carboxylate (TCV-116), were an...

The angiotensin II (AII) antagonistic action of azilsartan (AZL) [2-ethoxy-1-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1<i>H</i>-benzimidazole-7-carboxylic acid] was investigated in radioligand binding and function studies. AZL inhibited the specific ¹²⁵I-Sar¹-Ile⁸-AII to human type 1 receptors with an IC₅₀ 2.6 nM. inhibitory effect persisted after washout free compound (IC₅₀ value 7.4 nM). Olmesartan,...

A series of 2-substituted-1-[(biphenyl-4-yl)methyl]-1H-benzimidazole-7- carboxylic acids was prepared from the key intermediate 3-amino-2-[[(biphenyl-4- yl)methyl]amino]benzoate (6a-c) in order to clarify structure-activity relationships various analogues 2-butyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-ben zimidazole- 7-carboxylic acid (CV-11194), a potent and long acting angiotensin II (AII) receptor antagonist. The AII antagonistic activity benzimidazoles investigated by vitro...

A series of substituted 2-butylbenzimidazoles bearing a biphenylylmethyl moiety at the 1-position was prepared via three synthetic routes and evaluated for angiotensin II (AII) receptor antagonistic activity (in vitro in vivo). Binding affinity determined using bovine adrenal cortical membrane. Substitution 4-, 5-, or 6-position reduced relative to that unsubstituted compound (13a). However, most compounds with substituent 7-position showed binding comparable DuP 753 (losartan). In...

The antihypertensive effects of (+-)-(cyclohexyloxycarbonyloxy)ethyl2-ethoxy-1-[[2'-(1H- tetrazol-5- yl)biphenyl-4-yl]methyl]-1-H-benzimidazole-7-carboxylate (TCV-116), an angiotensin II (AII) subtype-1 receptor antagonist, were studied in various hypertensive and normotensive rats, using 2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)bip hen yl-4- yl)methyl]-imidazole, potassium salt (losartan) as a reference compound. TCV-116 is prodrug, which converted vivo to the active...

Coagulation enzyme factor Xa (FXa) is a particularly promising target for the development of new anticoagulant agents. We previously reported imidazo[1,5-c]imidazol-3-one derivative 1 as potent and orally active FXa inhibitor. However, it was found that predominantly undergoes hydrolysis upon incubation with human liver microsomes, specific metabolic pathway made difficult to predict pharmacokinetics. To address this issue, our synthetic efforts were focused on modification moiety metabolite...

The renin-angiotensin system (RAS) plays an important role in blood pressure regulation and electrolyte homeostasis. Angiotensin II (A II) is the principal active hormone of this blockade action A has been a target for development novel antihypertensive agents. In latter half 1970's, imidazoleacetic acid derivatives were synthesized discovered to be first nonpeptide antagonists. Structure-activity relationship study these compounds revealed that CV-2961 (17) had fairly strong receptor...

The coagulation enzyme factor Xa (FXa) has been recognized as a promising target for the development of new antithrombotic agents. We previously found compound 1 to be an orally bioavailable FXa inhibitor in fasted monkeys; however, showed poor bioavailability rats and fed monkeys. To work out pharmacokinetic problems, we focused our synthetic efforts on chemical conversion 4-(imidazo[1,2- a]pyridin-5-yl)piperazine moiety imidazolylpiperidine derivatives (fused nonfused), which resulted...

The action of the aspartyl protease renin is rate-limiting initial step renin-angiotensin-aldosterone system. Therefore, a particularly promising target for blood pressure as well onset and progression cardiovascular renal diseases. New pyrimidine derivatives 5-14 were designed in an attempt to enhance inhibitory activity compound 3 identified by our previous fragment-based drug design approach. Introduction basic amine essential interaction with two aspartic acids catalytic site...

Blockade of the action angiotensin II (AII) has long been a target for development novel antihypertensive agents. We recently discovered class potent nonpeptide AII receptor antagonists, benzimidazole-7-carboxylic acids including candesartan. Candesartan is highly and insurmountable type-1 (AT1)-selective antagonist. Structure-activity relationship (SAR) studies revealed that adjacent arrangement lipophilic substituent, tetrazolylbiphenylmethyl moiety carboxyl group was important structural...

Background: To ascertain the mechanism for rebound acid hypersecretion after treatment with an H2-receptor blocker, we investigated effects of ranitidine on gastric H+, K+-adenosine triphosphatase (ATPase) in rats, Methods: Male Wistar rats received (1-50mg/kg body weight intraperito-neally twice a day 5 days). The were starved 15 h last and then killed, vesicles containing K+-ATPase prepared. Results: Treatment dose-dependently increased protein content vesicular fraction purified from...

(3-Carboxy-5-oxo-5H[1]benzopyrano[2, 3-b]pyridin-2-yl)acetic acid derivatives (3 and 4) were found to possess potent antiarthritic activity in the rat adjuvant arthritis model. The mode of action these compounds differs from that acidic antiinflammatory drugs. Various modifications (e.g., elongation, removal, or substitution methylene group acetic moiety; benzene ring) made order study structure-activity relationships. However, it was structural requirements for show are rather severe.