- Design, synthesis and antihypertensive evaluation of novel codrugs with combined angiotensin type 1 receptor antagonism and neprilysin inhibition
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The multifactorial etiology of hypertension has promoted the research of blood pressure-lowering agents with multitarget actions to achieve better clinical outcomes. We describe here the discovery of novel dual-acting antihypertensive codrugs combining pharmacophores with angiotensin type 1 (AT1) receptor antagonism and neprilysin (NEP) inhibition. Specifically, the codrugs combine the AT1 antagonists losartan or its carboxylic acid active metabolite (E-3174) with selected monocarboxylic acid NEP inhibitors through a cleavable linker. The resulting codrugs exhibited high rates of in vitro conversion into the active molecules upon incubation with human/rat liver S9 fractions and in vivo conversion after oral administration in rodents. Moreover, the acute effects of one of the designed codrugs (3b) was confirmed at the doses of 10, 30 and 60 mg/kg p.o. in the spontaneous hypertensive rat (SHR) model, showing better antihypertensive response over 24 hours than the administration of an equivalent fixed-dose combination of 15 mg/kg of losartan and 14 mg/kg of the same NEP inhibitor used in 3b. The results demonstrate that the codrug approach is a plausible strategy to develop a single molecular entity with combined AT1 and NEP activities, aiming at achieving improved pharmacokinetics, efficacy and dosage convenience, as well as reduced drug-drug interaction for hypertension patients. In addition, the developability of the codrug should be comparable to the one of marketed AT1 antagonists, most of them prodrugs, but bearing only the AT1 pharmacophore.
- Mascarello, Alessandra,Azevedo, Hatylas,Ferreira Junior, Marcos Antonio,Ishikawa, Eloisa Eriko,Guimar?es, Cristiano Ruch Werneck
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Read Online
- Identification and Enzymatic Activity Evaluation of a Novel CYP2C9 Allelic Variant Discovered in a Patient
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Warfarin is a widely prescribed anticoagulant but the doses required to attain the optimum therapeutic effect exhibit dramatic inter-individual variability. Pharmacogenomics-guided warfarin dosing has been recommended to improve safety and effectiveness. We analyzed the cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) genes among 120 patients taking warfarin. A new coding variant was identified by sequencing CYP2C9. The novel A > G mutation at nucleotide position 14,277 led to an amino acid substitution of isoleucine with valine at position 213 (I213V). The functional consequence of the variant was subsequently evaluated in vitro. cDNA of the novel variant was constructed by site-directed mutagenesis and the recombinant protein was expressed in vitro using a baculovirus–insect cell expression system. The recombinant protein expression was quantified at apoprotein and holoprotein levels. Its enzymatic activities toward tolbutamide, warfarin and losartan were then assessed. It exhibited changed apparent Km values and increases of 148%, 84% and 67% in the intrinsic clearance of tolbutamide, warfarin and losartan, respectively, compared to wild-type CYP2C9*1, indicating dramatically enhanced in vitro enzymatic activity. Our study suggests that the amino acid at position 213 in wild-type CYP2C9*1 may be important for the enzymatic activity of CYP2C9 toward tolbutamide, warfarin and losartan. In summary, a patient taking high-dose warfarin (6.0?mg/day) in order to achieve the target international normalized ratio was found to have a mutation in the CYP2C9 gene.
- Zhou, Xiao-Yang,Lu, Xiang-Ran,Li, Ying-Hui,Ma, Ya-Qing,Zhao, Shi-Wen,Wang, Fang,Xu, Ren-Ai,Hu, Guo-Xin,Cai, Jian-Ping
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- MANUFACTURING METHOD OF LOSARTAN METABOLITE EXP-3174
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The present invention provides a manufacturing method capable of manufacturing a losartan metabolite EXP-3174 with high purity and high yield using inexpensive starting materials and under mild reaction conditions. The losartan metabolite EXP-3174 is represented by chemical formula 5.
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Paragraph 0073-0075; 0082-0084
(2020/09/30)
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- A process for preparing a renin - angiotensin - aldosterone system dual inhibitor compound of intermediate
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The invention relates to an intermediate compound for preparing RAAS (renin-angiotensin-aldosterone system) dual inhibitor compounds. RAAS dual inhibitors can be used for treating diseases related to an RAAS such as high blood pressure and heart diseases.
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Paragraph 0119; 0120; 0121
(2017/04/28)
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- Preparing method for EXP-3174
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The invention discloses a preparing method for EXP-3174. The preparing method is characterized in that losartan is used as a starting raw material and is prepared into EXP-3174 through two-step oxidation. The preparing method has the greatest advantages that a reaction is moderate, the number of side reactions is small, aftertreatment is simple, and EXP-3174 with the purity of 99.9% can be obtained without column chromatography isolation.
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Paragraph 0016
(2016/10/09)
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- RAAS system as a dual inhibitor compounds
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The invention discloses a compound used as a dual inhibitor for RAAS (rennin angiotensin aldosterone system) and particularly relates to a compound shown in formula (I), a stereisomer thereof or a pharmaceutically acceptable salt thereof. The compound can be used for treating and blocking RAS-associated diseases such as hypertension and heart disease, can be used for preventing or treating hypertension, congestive heart failure, pulmonary hypertension, renal insufficiency, renal ischemia, kidney failure, renal fibrosis, cardiac insufficiency, cardiac hypertrophy, cardiac fibrosis, myocardial ischemia, cardiomyopathy, glomerulonephritis, renal colic, complications such as nephropathy caused by diabetes, vasculopathy, vasculopathy, glaucoma, intraocular pressure elevation, atherosis, restenosis after revascularization, complications after blood vessel or cardiac operation, erectile dysfunction, hyperaldosteronism, lung fibrosis, scleroderma, anxiety, cognitive disorder, complications caused by immunosuppressor treatment as well as other known diseases associated with the rennin angiotensin aldosterone system.
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Paragraph 0042-0044
(2017/02/28)
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- New losartan-hydrocaffeic acid hybrids as antihypertensive-antioxidant dual drugs: Ester, amide and amine linkers
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We report new examples of a series of losartan-hydrocaffeic hybrids that bear novel ester, amide and amine linkers. These compounds were made by linking hydrocaffeic acid to the side chain of losartan at the C-5 position of the imidazole ring through different strategies. Experiments performed in cultured cells demonstrate that these new hybrids retain the ability to block the angiotensin II effect and have increased antioxidant ability. Most of them reduced arterial pressure in rats better or as much as losartan.
- García, Gonzalo,Serrano, Isabel,Sánchez-Alonso, Patricia,Rodríguez-Puyol, Manuel,Alajarín, Ramón,Griera, Mercedes,Vaquero, Juan J.,Rodríguez-Puyol, Diego,álvarez-Builla, Julio,Díez-Marqués, María L.
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experimental part
p. 90 - 101
(2012/07/13)
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- ANGIOTENSIN II RECEPTOR ANTAGONISTS
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A compound having the structure (A) wherein R is an angiotensin receptor antagonist active group, and Y is 1) -(CH2)3R5, 2) -C(O)(CH2)2R5, 3) -C(R1R2)OC(O)O(CH2)nR5, wherein n is 1 or 2, 4) -C(R1R2)OC(O)CH2CH2R5, 5) -C(R1R2)OC(O)OCH2CH2C(R3R4)R5, Formula (B), and Formula (C) provided that when Y is -C(O)(CH2)2R5, then R is Formula (D) R1, R2, R3 and R4 are independently selected from the group consisting of hydrogen and C1-4 alkyl; R5 is CH(ONO2)CH(ONO2)R6; R6 is selected from CH3, CH2CH3 and CH(CH3)2; or a pharmaceutically acceptable salt or hydrate thereof, which is useful for treating hypertension.
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Page/Page column 20
(2009/07/03)
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- NEW ANGIOTENSIN II RECEPTOR BLOCKER DERIVATIVES
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New angiotensin II receptor blocker nitroderivatives of general formula (I) and pharmaceutically acceptable salts or stereoisomers thereof: and their use for treating cardiovascular, renal and chronic liver diseases, inflammatory processes and metabolic syndromes.
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Page/Page column 191-192
(2009/10/21)
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- ANGIOTENSIN II RECEPTOR ANTAGONISTS
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The present invention relates to nitrooxyderivatives of angiotensin II receptor antagonist having the general formula (I): where in R is selected f rom the group consisting of (IIa) - (IIk): when R is selected from (Ilk), Y is selected from the group consisting of: 1) -C(O) (CH2) nR5; 2) -C(O)(CH2n-O-CH2-R5; 3) -C(O)-R6 wherein R6 is the following group: when R is selected from (IIa)-(IIh), Y is selected from the group consisting of: 4) -C(R1R2)OC(O)-(CH2)nR5; 5) -C(R1R2)OC(O)O-(CH2)nR5; 6) C(R1R2)OC(O)(CH2)n-O-CH2-R5; 7) C(R1R2)OC(O)O(CH2)n-O-CH2-R5; 8) -C(R1R2)OC(O)-R6 wherein R6 is as above defined; R1 and R2 are independently selected from the group consisting of hydrogen and C1-4 alkyl; R5 is -CH(ONO2)R7; R7 is CH3 or C1-4 alkyl; n is an integer from 1 to 4; or a pharmaceutically acceptable salt thereof.
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Page/Page column 37
(2009/10/21)
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- ANGIOTENSIN II RECEPTOR ANTAGONISTS
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A compound having the structure wherein R is, for example, Y is selected from the group consisting of 1) R5, 2) -C(R1R2)(C(R3R4))0-1Y1R5, and 3) -C(R1R2)-O-Y1R5; R1, R2, R3 and R4 are independently selected from the group consisting of hydrogen and C1-4 alkyl; R5 is; Y1 is selected from the group consisting of C(O)-O- and P(O)(OR6)-O-; and R6 is hydrogen or CH3, or a pharmaceutically acceptable salt thereof, and methods of using the compounds for treating hypertension.
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Page/Page column 11; 12
(2009/12/23)
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- ANGIOTENSIN II RECEPTOR ANTAGONISTS
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A compound having the structure (I) wherein R is an angiotensin II receptor antagonist selected from the group consisting of (IIa)- (IIh); A is (Formula) wherein Rl and R2 are independently selected from the group consisting of hydrogen and C1-4 alkyl. Y is X0-Z wherein X0 is selected from the group consisting of: -O-, -O-CO-, -OCOO-, -OCONH- and -OSO2-; Z is a nitric oxide releasing moiety, or a pharmaceutically acceptable salt thereof.
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Page/Page column 67
(2010/01/07)
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- Imidazole-5-Carboxylic Acid Derivatives, The Preparation Method Therefor and The Uses Thereof
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The invention discloses imidazole-5-carboxylic acid derivatives, and their preparation methods. The derivatives of the invention are Angiotensin II receptor antagonists with angiotensin II antagonistic activity and antihypertensive activity, and thereby can be used as a therapeutical agent to treat hypertension.
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Page/Page column 8
(2009/04/24)
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- IMIDAZOL-5-CARBOXYLIC ACID DERIVATIVES, PREPARATION METHODS AND USE THERROF
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The invention discloses imidazole-5-carboxylic acid derivatives, and their preparation methods. The derivatives of the invention are Angiotensin II receptor antagonists with angiotensin II antagonistic activity and antihypertensive activity, and thereby can be used as a therapeutical agent to treat hypertension.
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Page/Page column 11
(2008/12/08)
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- Cardiovascular agents
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The present invention relates to novel compounds that are derivatives of angiotensin receptor blocker (ARB) that comprise in their formula a polysulfurated group and that are useful for treating cardio-vascular diseases, such as hypertension, ischemic heart disease, atherosclerosis, metabolic syndrome, etc. also in combination with other cardiovascular agents.
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Page/Page column 9
(2008/12/04)
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- ANGIOTENSIN II RECEPTOR ANTAGONISTS
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A compound having the structure (Formula I), wherein R is an angiotensin receptor antagonist active group, Y is -Y1-Y2-Y3-Y4-Y5.; Y1 is C(R1R2); R1 is selected from the group consisting of hydrogen and C1-4 alkyl; R2 is selected from the group consisting of hydrogen, C1-4 alkyl, and -0C(0)C1-4 alkyl; Y2 is O or CH2; Y3 is C(O) or CH2; Y4 is O or CH2; Y5 is -(CH2) 1-2-(X)0-l-(CH2)0-l- or is absent; X is -O- or - CR3R4-; and R3 and R4 are independently selected from the group consisting of hydrogen and C1-C4 alkyl; or a pharmaceutically acceptable salt or hydrate thereof, which is useful for treating hypertension.
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Page/Page column 21
(2008/12/06)
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- Preparation of losartan 5-carboxylic acid and use thereof
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A method for synthesis of losartan 5-carboxylic acid (EXP-3174).
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Page/Page column 2
(2008/06/13)
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- ANGIOTENSIN II RECEPTOR ANTAGONISTS
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The compounds of the present invention are polymorphic crystalline forms of the compound 2-butyl-4-chloro-1-[(2’-(1-H-tetrazol-5-yl)biphenyl-4-yl)methyl]-imidazole-5-carboxylic acid, which has the structure (I). Specifically, the compounds of the invention are selected from the group consisting of 2-butyl-4-chloro-1-[(2’-(1-H-tetrazol-5-yl)biphenyl-4-yl)methyl]-imidazole-5-carboxylic acid of Claim 3 selected from the group consisting of 2-butyl-4-chloro-1-[(2’-(1-H-tetrazol-5-yl)biphenyl-4-yl)methyl]-imidazole-5-carboxylic acid hydrochloride Form I, 2-butyl-4-chloro-1-[(2’-(1-H-tetrazol-5-yl)biphenyl-4-yl)methyl]-imidazole-5-carboxylic acid hydrochloride Form II, 2-butyl-4-chloro-1-[(2’-(1-H-tetrazol-5-yl)biphenyl-4-yl)methyl]-imidazole-5-carboxylic acid hydrochloride Form III, and 2-butyl-4-chloro-1-[(2’-(1-H-tetrazol-5-yl)biphenyl-4-yl)methyl]-imidazole-5-carboxylic acid monohydrate Form IV, 2-butyl-4-chloro-1-[(2’-(1-H-tetrazol-5-yl)biphenyl-4-yl)methyl]-imidazole-5-carboxylic acid monohydrate Form V, 2-butyl-4-chloro-1-[(2’-(1-H-tetrazol-5-yl)biphenyl-4-yl)methyl]-imidazole-5-carboxylic acid monohydrate Form VI, 2-butyl-4-chloro-1-[(2’-(1-H-tetrazol-5-yl)biphenyl-4-yl)methyl]-imidazole-5-carboxylic acid monohydrate Form VII, and 2-butyl-4-chloro-1-[(2’-(1-H-tetrazol-5-yl)biphenyl-4-yl)methyl]-imidazole-5-carboxylic acid monohydrate Form VIII.
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Page/Page column 12-13
(2008/06/13)
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- New NO-releasing pharmacodynamic hybrids of losartan and its active metabolite: Design, synthesis, and biopharmacological properties
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In a preliminary work, we reported two NO-sartans, possessing the characteristics of an AT1 antagonist and a "slow NO donor", obtained by adding NO-donor side chains to losartan 1. The NO release from an NO-sartan should be modulated in order to strengthen the antihypertensive activity of the native drug and to ensure additional effects, such as the antiplatelet and anti-ischemic ones. To obtain a collection of proto-typical NO-sartans, showing different rates of NO release, new NO-donor moieties have been linked to 1 or its active metabolite 2 (EXP 3174). Almost all the synthesized compounds exhibited both AT1-antagonist and NO-mediated vasorelaxing properties, with a wide range of NO-releasing rates. Further pharmacological investigation on compound 4a showed that it possessed antihypertensive and cardiac antihypertrophic effects similar to those of the reference AT1-blocking or ACE-inhibiting drugs. Furthermore, the additional anti-ischemic cardio-protective properties and antiplatelet effects of 4a have been preliminarily investigated.
- Breschi, Maria C.,Calderone, Vincenzo,Digiacomo, Maria,Macchia, Marco,Martelli, Alma,Martinotti, Enrica,Minutolo, Filippo,Rapposelli, Simona,Rossello, Armando,Testai, Lara,Balsamo, Aldo
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p. 2628 - 2639
(2007/10/03)
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- A convenient synthesis by microwave irradiation of an active metabolite (EXP-3174) of losartan
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A novel and convenient microwave-assisted synthesis of an active metabolite (EXP-3174) of losartan is described. Room temperature and microwave irradiation of the reactions are compared. Synthesis by microwave irradiation gave the desired compound in higher yields and in shorter reaction times than those obtained at room temperature.
- Santagada, Vincenzo,Fiorino, Ferdinando,Perissutti, Elisa,Severino, Beatrice,Terracciano, Sara,Teixeira, Cleber Evandro,Caliendo, Giuseppe
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p. 1149 - 1152
(2007/10/03)
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- ANGIOTENSIN II RECEPTOR BLOCKING IMIDAZOLES
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Substituted imidazoles such as STR1 are useful as angiotensin II blockers. These compounds have activity in treating hypertension and congestive heart failure.
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- Treatment of central nervous system disorders with imidazole angiotensin-II receptor antagonists
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Substituted imidazoles such as 2-butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-5-(hydroxymethyl)imidazole and 2-butyl-4-chloro-1-[(2'-carboxybiphenyl-4-yl)-methyl]-5-(hydroxymethyl)imidazole and pharmaceutically acceptable salts thereof are useful for treating central nervous system disorders, such as cognitive and learning disorders, mediated by angiotensin II.
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- Treatment of congestive heart failure with angiotensin 11 receptor blocking imidazoles
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Substituted imidazoles such as STR1 are useful as angiotensin II blockers. These compounds have activity in treating hypertension and congestive heart failure.
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