- Small Cause, Great Impact: Modification of the Guanidine Group in the RGD Motif Controls Integrin Subtype Selectivity
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Due to its unique role as a hydrogen-bond donor and its positive charge, the guanidine group is an important pharmacophoric group and often used in synthetic ligands. The chemical modification of the guanidine group is often considered to destroy its function. Herein, we show that the N-methylation, N-alkylation, or N-acylation of the guanidine group can be used to modify the receptor subtype specificity of the integrin ligand cilengitide. Using the αvβ6/α5β1-biselective ligand c(isoDGRkphg) and the αvβ6-specific ligand c(FRGDLAFp(NMe)K(Ac) as examples, we show that the binding affinities of the ligands can be fine-tuned by this method to enhance the selectivity for αvβ6. Furthermore, we describe a new strategy for the functionalization of integrin ligands. By introducing longer N-alkylguanidine and N-acylguanidine groups, we are able to simultaneously identify a hitherto unknown anchoring point and enhance the subtype selectivity of the ligand.
- Kapp, Tobias G.,Fottner, Maximilian,Maltsev, Oleg V.,Kessler, Horst
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Read Online
- Discovery of acylguanidine oseltamivir carboxylate derivatives as potent neuraminidase inhibitors
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In search of novel anti-influenza agents with higher potency, a series of acylguanidine oseltamivir carboxylate analogues were synthesized and evaluated against influenza viruses (H1N1 and H3N2) in vitro. The representative compounds with strong inhibitory activities (IC50 40?nM) against neuraminidase (NA) were further tested against the NA from oseltamivir-resistant strain (H259Y). Among them, compounds 9 and 17 were potent NA inhibitors that exhibited a 5 and 11-fold increase in activity comparing with oseltamivir carboxylate (2, OC) against the H259Y mutant, respectively. Furthermore, the effect against influenza virus H259Y mutant (H1N1) replication and cytotoxicity assays indicated that compounds 9 and 17 exhibited a 20 and 6-fold increase than the parent compound 2, and had no obvious cytotoxicity in vitro. Moreover, the molecular docking studies revealed that the docking modes of compounds 9 and 17 were different from that of oseltamivir, and the new hydrogen bonds and hydrophobic interaction were formed in this case. This work provided unique insights in the discovery of potent inhibitors against NAs from wild-type and oseltamivir-resistant strains.
- Li, Zhaoliang,Meng, Yanchun,Xu, Shengtao,Shen, Wang,Meng, Zhaoqing,Wang, Zhenzhong,Ding, Gang,Huang, Wenzhe,Xiao, Wei,Xu, Jinyi
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Read Online
- Design, synthesis biological activity, and docking of novel fluopyram derivatives containing guanidine group
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Succinate dehydrogenase (SDH), a crucial bridge enzyme between the respiratory electron transfer chain and tricarboxylic acid (or Krebs) cycle, has been identified as an ideal target for the development of effective fungicide. In this study, a series of 24 novel SDH inhibitors (SDHIs) were designed, synthesized, and characterized by 1H NMR, 13C NMR, and HRMS. In vitro fungicidal activity experiments, most of the compounds exhibited broad-spectrum antifungal activities against five plant pathogenic fungi. Compounds 9j and 9k showed excellent activities against Pythium aphanidermatum with EC50 values of 9.93 mg/L and 10.50 mg/L, respectively, which were superior to the lead compound Fluopyram with an EC50 value of 19.10 mg/L. Furthermore, the toxicity of these compounds was also tested against Meloidogyne incognita J2 nematodes. The results indicated that compound 9x exhibited moderate nematicidal activity (LC50/48 h = 71.02 mg/L). Molecular docking showed that novel guanidine amide of 9j formed hydrogen bonds with crucial residues, which was crucial to the binding of an inhibitor and SDH. This present work indicates that these derivatives may serve as novel potential fungicides targeting SDH.
- Liang, Peibo,Shen, Shengqiang,Xu, Qingbo,Wang, Simin,Jin, Shuhui,Lu, Huizhe,Dong, Yanhong,Zhang, Jianjun
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- METHODS OF TREATING CREATINE TRANSPORTER DEFICIENCY
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Disclosed are methods of treating creatine transporter deficiency, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound that increases transport of a substrate by a mutant or wild-type creatine transporter. Also disclosed are methods of increasing transport of guanidinoacetic acid or a salt thereof across the blood-brain barrier of a mammal, and methods of decreasing accumulation or the concentration of guanidinoacetic acid or a salt thereof in a mammalian cell.
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Paragraph 0383-0384
(2021/10/02)
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- SMALL MOLECULES TARGETING MUTANT MAMMALIAN PROTEINS
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Disclosed are compounds, compositions, and methods useful for treating or preventing a disease or disorder associated with a mutation in a protein.
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Paragraph 0522-0523
(2021/12/03)
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- ANALGESIC AND ANTI-ADDICTIVE COMPOSITIONS FOR TREATMENT OF CHRONIC PAIN AND OPIOID ADDICTION
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The invention provides a compound of formula I and stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and with the substituents and structural features described herein. Also described are pharmaceutical compositions and medicaments t
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Page/Page column 28-30
(2020/06/10)
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- CXCR4-TARGETED DIAGNOSTIC AND THERAPEUTIC AGENTS WITH REDUCED SPECIES SELECTIVITY
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The present disclosure relates to imaging and endoradiotherapy of diseases involving chemokine receptor 4 (CXCR4). Provided are compounds which bind or inhibit hCXCR4 and mCXCR4 and furthermore carry at least one moiety which is amenable to labeling. Provided are also medical uses of such compounds.
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Page/Page column 63
(2020/05/07)
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- Regioselective microwave synthesis and derivatization of 1,5-diaryl-3-amino-1,2,4-triazoles and a study of their cholinesterase inhibition properties
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Herein we describe the development of an efficient one-pot regioselective synthesis protocol to obtain N-protected or N-deprotected 1,5-diaryl-3-amino-1,2,4-triazoles from N-acyl-N-Boc-carbamidothioates. This improved protocol using microwave irradiation and low reaction times (up to 1 h) furnished desired compounds in yields ranging from 50 to 84%. This chemistry is useful for a variety of aromatic groups with electronically diverse substituents. The design and correct derivation of the amino group led to compounds able to inhibit cholinesterases with good IC50 of up to 1 μM. Also, the mode of action (mixed-type) and SAR analysis for this series of compounds was described by means of kinetic and molecular modelling evaluations, showing potential for this class of compounds as new scaffolds for this biological activity.
- Santos, Sabrina Neves,Alves De Souza, Gabriela,Pereira, Thiago Moreira,Franco, Daiana Portella,De Nigris Del Cistia, Catarina,Sant'anna, Carlos Mauricio R.,Lacerda, Renata Barbosa,Kümmerle, Arthur Eugen
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p. 20356 - 20369
(2019/07/09)
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- GUANIDINE DERIVATIVE AND MEDICAL USE THEREOF
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A compound has a guanidine skeleton that inhibits the protease activity of MALT1 and exerts a therapeutic or prophylactic effect on autoimmune disease such as psoriasis or allergic disease such as atopic dermatitis. The guanidine derivative is typified by the following formula or a pharmacologically acceptable salt thereof.
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Paragraph 0503-0505
(2019/08/22)
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- Compound, and preparation method and application thereof
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The invention provides a compound, and a preparation method and an application thereof. The compound can be used as a neuraminidase inhibitor. Experimental results show that the compound has a stronginhibitory effect on neuraminidases of H1N1, H3N2 and H259Y(H1N1) influenza viruses, and especially has a better or same inhibitory effect on the neuraminidase of the H259Y(H1N1) influenza virus thana positive drug oseltamivir carboxylate. The compound has a high activity, and can be used for preparing a neuraminidase inhibitor, and the preparation method of the compound has the advantages of simplicity, easily available raw materials and low cost.
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Paragraph 0058; 0060; 0067
(2020/04/02)
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- Acylguanidine derivatives of zanamivir and oseltamivir: Potential orally available prodrugs against influenza viruses
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Zanamivir (ZA) and guanidino-oseltamivir carboxylic acid (GOC) are very potent inhibitors against influenza neuraminidase (NA). The guanidinium moiety plays an important role in NA binding; however, its polar cationic nature also hinders the use of ZA and GOC from oral administration. In this study, we investigated the use of ZA and GOC acylguanidine derivatives as possible orally available prodrugs. The acylguanidine derivatives were prepared by coupling with either n-octanoic acid or (S)-naproxen. The lipophilic acyl substituents were verified to improve cell permeability, and may also improve the bioavailability of acylguanidine compounds. In comparison, the acylguanidines bearing linear octanoyl chain showed better NA inhibitory activity and higher hydrolysis rate than the corresponding derivatives having bulky branched naproxen moiety. Our molecular docking experiments revealed that the straight octanoyl chain could extend to the 150-cavity and 430-cavity of NA to gain extra hydrophobic interactions. Mice receiving the ZA octanoylguanidine derivative survived from influenza infection better than those treated with ZA, whereas the GOC octanoylguanidine derivative could be orally administrated to treat mice with efficacy equal to oseltamivir. Our present study demonstrates that incorporation of appropriate lipophilic acyl substituents to the polar guanidine group of ZA and GOC is a feasible approach to develop oral drugs for influenza therapy.
- Hsu, Peng-Hao,Chiu, Din-Chi,Wu, Kuan-Lin,Lee, Pei-Shan,Jan, Jia-Tsrong,Cheng, Yih-Shyun E.,Tsai, Keng-Chang,Cheng, Ting-Jen,Fang, Jim-Min
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p. 314 - 323
(2018/05/29)
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- A novel method to synthesize phosphocreatine and phosphocreatine prodrugs
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Background: Adenosine triphosphate (ATP) is the energy currency of the body; it takes part in various and indispensable metabolic processes for the maintenance of cell homeostasis, degrading to its hydrolysis product, adenosine diphosphate (ADP). Efficient ways to restore ATP are therefore necessary in the cells. When the cell lacks energy due to ischemic conditions or high ATP demand, phosphocreatine gives its phosphate group to ADP that converts to ATP, in a reaction catalyzed by the enzyme creatine kinase. For this reason, phosphocreatine is utilized as a pharmacological treatment in human diseases that involve a failure of the cellular energy, most notably in coronary artery disease. Objective: Commercially available phosphocreatine is currently synthesized using different methods, each of one characterized by a rather low yield of the final product, probably due to the low reactivity of the guanylating reagent. The aim of this work is to overcome the drawbacks of the synthetic methods currently employed, devising a novel synthetic route to obtain phosphocreatine and phosphocreatine prodrugs in higher yields and purity. Method: To obtain a higher yield of the final product and a lower number of sub-products, this method utilizes a new guanylating agent characterized by high reactivity, endowed with a protecting group t-Boc on one of the two nitrogen atoms of the guanidinic function and a protected phosphate on the other one; that compound is then conjugated with an opportune secondary amine. The obtained product is cleaved first with acidic conditions to obtain the phosphocreatine prodrug (phosphocreatine ethyl ester) and then with an enzymatic method to obtain the phosphocreatine. Results: Have been obtained in good yield and purity as demonstrated by HPLC and mass spec-trometry analysis. Conclusion: This novel synthetic route permits to obtain the phosphocreatine molecule in higher yield and purity compared to the methods currently employed with a combination of chemical and enzymatic methods.
- Arkel, Maria,Garbati, Patrizia,Salis, Annalisa,Damonte, Gianluca,Liessi, Nara,Adriano, Enrico,Benatti, Umberto,Balestrino, Maurizio,Millo, Enrico
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- Aroyl guanidyl oseltamivir carboxylic acid derivative as well as preparation method and application thereof
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The invention discloses an oseltamivir guanidyl carboxylic acid derivative as shown in the general formula I, and particularly relates to an aroyl guanidyl oseltamivir carboxylic acid derivative as well as a preparation method and application thereof. The compound disclosed by the invention shows high suppression activity for neuraminidase of wild and mutant type influenza viruses, and can be used for preparing a medicine for preventing and/or treating diseases caused by the influenza viruses.
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Paragraph 0026
(2017/08/29)
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- DIPHENYL PYRAZOLE DERIVATIVE AND PHARMACEUTICAL USE THEREOF
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PROBLEM TO BE SOLVED: To provide a compound that functions to inhibit MALT1 protease activity and is useful as an agent for treating or for preventing autoimmune disease such as multiple sclerosis and psoriasis. SOLUTION: The present invention provides a diphenyl pyrazole derivative represented by the following formula or a pharmacologically acceptable salt thereof. SELECTED DRAWING: None COPYRIGHT: (C)2018,JPO&INPIT
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Paragraph 0131; 0133
(2018/02/28)
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- COMPOUNDS FOR TREATMENT OF CYSTIC FIBROSIS
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Described herein are compounds, compositions, and methods of their use for the treatment of cystic fibrosis.
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Paragraph 00223
(2015/01/16)
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- Compositions for Treatment of Cystic Fibrosis and Other Chronic Diseases
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The present invention relates to pharmaceutical compositions comprising an inhibitor of epithelial sodium channel activity in combination with at least one ABC Transporter modulator compound of Formula A, Formula B, Formula C, or Formula D. The invention also relates to pharmaceutical formulations thereof, and to methods of using such compositions in the treatment of CFTR mediated diseases, particularly cystic fibrosis using the pharmaceutical combination compositions.
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Paragraph 2459
(2015/09/22)
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- ENHANCED ANTI-INFLUENZA AGENTS CONJUGATED WITH ANTI-INFLAMMATORY ACTIVITY
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Novel dual-targeted, bifunctional anti-influenza drugs formed by conjugation with anti-inflammatory agents are disclosed. Exemplary drugs according to the invention include caffeic acid (CA)-bearing zanamivir (ZA) conjugates ZA-7-CA (1), ZA-7-CA-amide (7) and ZA-7-Nap (43) for simultaneous inhibition of influenza virus neuraminidase and suppression of proinflammatory cytokines. Synthetic methods for preparation of these enhanced anti-influenza conjugate drugs are provided. The synthetic bifunctional ZA conjugates act synergistically towards protection of mice lethally infected by H1N1 or H5N1 influenza viruses. The efficacy of ZA-7-CA, ZA-7-CA-amide and ZA-7-Nap conjugates is much greater than the combination therapy of ZA with anti-inflammatory agents.
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Paragraph 0304
(2013/10/22)
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- Improved synthesis of no-carrier-added [*I]MIBG and its precursor
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3-(Trimethylstannyl)benzyl alcohol was coupled in a Mitsunobu reaction with bis(Boc)-guanidine to give bis(Boc)-protected 3-(trimethylstannyl) benzylguanidine used as precursor for [*I]MIBG. Radioiodination with [131I]iodine generated from [131I]NaI and chloramine-T, removal of Boc groups, and purification by HPLC gave no-carrier-added tracer [*I]MIBG (81% radiochemical yield, 99% chemical purity) used for imaging tumors of neuroendocrine origin. The structures of bis(Boc)-guanidine and bis(Boc)-protected 3-(trimethylstannyl)benzylguanidine were secured by single crystal X-ray structure analyses.
- Hammerschmidt, Friedrich,Schweifer, Anna,Kvaternik, Herbert,Aigner, Reingard M.,Mereiter, Kurt
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p. 3387 - 3391,5
(2012/12/12)
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- Improved synthesis of no-carrier-added [*I]MIBG and its precursor
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3-(Trimethylstannyl)benzyl alcohol was coupled in a Mitsunobu reaction with bis(Boc)-guanidine to give bis(Boc)-protected 3-(trimethylstannyl) benzylguanidine used as precursor for [*I]MIBG. Radioiodination with [131I]iodine generated from [131I]NaI and chloramine-T, removal of Boc groups, and purification by HPLC gave no-carrier-added tracer [*I]MIBG (81% radiochemical yield, 99% chemical purity) used for imaging tumors of neuroendocrine origin. The structures of bis(Boc)-guanidine and bis(Boc)-protected 3-(trimethylstannyl)benzylguanidine were secured by single crystal X-ray structure analyses.
- Hammerschmidt, Friedrich,Kvaternik, Herbert,Schweifer, Anna,Mereiter, Kurt,Aigner, Reingard M.
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p. 3387 - 3391
(2013/01/15)
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- Acyl guanidine inhibitors of β-secretase (bACE-1): Optimization of a micromolar hit to a nanomolar lead via iterative solid- and solution-phase library synthesis
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This report describes the discovery and optimization of a BACE-1 inhibitor series containing an unusual acyl guanidine chemotype that was originally synthesized as part of a 6041-membered solid-phase library. The synthesis of multiple follow-up solid- and
- Gerritz, Samuel W.,Zhai, Weixu,Shi, Shuhao,Zhu, Shirong,Toyn, Jeremy H.,Meredith, Jere E.,Iben, Lawrence G.,Burton, Catherine R.,Albright, Charles F.,Good, Andrew C.,Cook, Lynda S.,Padmanabha, Ramesh,Lentz, Kimberley A.,Sofia, Michael J.,MacOr, John E.,Thompson, Lorin A.,Tebben, Andrew J.,Muckelbauer, Jodi K.,Camac, Daniel M.,Metzler, William,Poss, Michael A.
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p. 9208 - 9223,16
(2020/10/15)
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- BENZOXEPIN PI3K INHIBITOR COMPOUNDS AND METHODS OF USE
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Benzoxepin compounds of Formula I, and including stereoisomers, geometric isomers, tautomers, solvates, metabolites and pharmaceutically acceptable salts thereof, wherein: Z1 is CR1 or N; Z2 is CR2 or N; Z3 is CR3 or N; Z4 is CR4 or N; and where (i) X1 is N and X2 is S, (ii) X1 is S and X2 is N, (iii) X1 is CR7 and X2 is S, (iv) X1 is S and X2 is CR7; (v) X1 is NR8 and X2 is N, (vi) X1 is N and X2 is NR8, (vii) X1 is CR7 and X2 is O, (viii) X1 is O and X2 is CR7, (ix) X1 is CR7 and X2 is C(R7)2, (x) X1 is C(R7)2 and X2 is CR7; (xi) X1 is N and X2 is O, or (xii) X1 is O and X2 is N, are useful for inhibiting lipid kinases including p110 alpha and other isoforms of PI3K, and for treating disorders such as cancer mediated by lipid kinases. Methods of using compounds of Formula I for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.
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Page/Page column 238
(2011/04/19)
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- Application of the guanidine-acylguanidine bioisosteric approach to argininamide-type NPY Y2 receptor antagonists
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Strongly basic groups such as guanidine moieties are crucial structural elements, but they compromise the drug-likeness of numerous biologically active compounds, including ligands of G-protein-coupled receptors (GPCRs). As part of a project focused on the search for guanidine bioisosteres, argininamide-type neuropeptideY (NPY) Y2 receptor (Y2R) antagonists related to BIIE0246 were synthesized. Starting from ornithine derivatives, NG-acylated argininamides were obtained by guanidinylation with tailor-made mono-Boc-protected N-acyl-S-methylisothioureas. The compounds were investigated for Y2R antagonism (calcium assays), Y2R affinity, and NPY receptor subtype selectivity (flow cytometric binding assays). Most of the NG-substituted (S)-argininamides showed Y2R antagonistic activities and binding affinities similar to those of the parent compound, whereas NG-acylated or -carbamoylated analogues with a terminal amine were superior (Y2R: Ki and KB values in the low nanomolar range). This demonstrates that the basicity of the compounds, although 4-5 orders of magnitude lower than that of guanidines, is sufficient to form key interactions with acidic amino acids of the Y2R. The acylguanidines bind with high affinity and selectivity to Y2R over the Y1, Y4, and Y5 receptors. As derivatization of the amino group is tolerated, these compounds can be considered building blocks for the preparation of versatile fluorescent and radiolabeled pharmacological tools for invitro studies of the Y2R. The results support the concept of bioisosteric guanidine-acylguanidine exchange as a broadly applicable approach to retain pharmacological activity despite decreased basicity.
- Pluym, Nikola,Brennauer, Albert,Keller, Max,Ziemek, Ralf,Pop, Nathalie,Bernhardt, Guenther,Buschauer, Armin
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scheme or table
p. 1727 - 1738
(2012/01/14)
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- NG-Acyl-argininamides as NPY Y1 receptor antagonists: Influence of structurally diverse acyl substituents on stability and affinity
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NG-Acylated argininamides, covering a broad range of lipophilicity (calculated log D values: -1.8-12.5), were synthesized and investigated for NPY Y1 receptor (Y1R) antagonism, Y 1R affinity and stability in buffer (NG-deacylation, yielding BIBP 3226). Broad structural variation of substituents was tolerated. The Ki (binding) and Kb values (Y1R antagonism) varied from low nM to one-digit μM. Most of the compounds proved to be sufficiently stable at pH 7.4 over 90 min to determine reliable pharmacological data in vitro. Exceptionally high instability was detected when a succinyl moiety was attached to the guanidine, probably, due to an intramolecular cleavage mechanism.
- Weiss, Stefan,Keller, Max,Bernhardt, Günther,Buschauer, Armin,K?nig, Burkhard
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scheme or table
p. 6292 - 6304
(2010/10/19)
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- Organic Compounds
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A compound of Formula I in free or salt or solvate form, where R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 and R11 have the meanings as indicated in the specification, is useful for treating diseases which respond to the blockade of the epithelial sodium channel. Pharmaceutical compositions that contain the compounds and processes for preparing the compounds are also described.
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Page/Page column 107
(2010/06/14)
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- Modular synthesis of non-peptidic bivalent NPY Y1 receptor antagonists
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According to a 'bivalent ligand approach' to increase the affinity of the potent argininamide-type NPY Y1 receptor antagonist BIBP-3226, dimeric ligands were synthesized in which two molecules of the parent compound were linked by different spacers via NG-acylation at the guanidino groups. A synthetic route for the preparation of the title compounds was developed, which includes a copper(I)-catalyzed azide alkyne cycloaddition as the key step. Three bivalent analogues of BIBP-3226 were prepared showing nanomolar antagonistic activity and binding affinity to the NPY Y1 receptor (calcium assay on HEL cells, radioligand binding assay on SK-N-MC cells), but these ligands were not superior to the parent compound and there was no correlation with the length or the chemical nature of the spacer. A trivalent BIBP-3226 derivate showed, surprisingly, no affinity to the NPY Y1 receptor at all.
- Weiss, Stefan,Keller, Max,Bernhardt, Guenther,Buschauer, Armin,Koenig, Burkhard
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experimental part
p. 9858 - 9866
(2009/04/06)
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- ORGANIC COMPOUNDS
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A compound of formula (I), or tautomers, or stereoisomers, or solvates, or pharmaceutically acceptable salts thereof, wherein M1, M2, L1, L2, W1, W2, X1, X2, Y1/
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Page/Page column 39
(2009/01/20)
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- Macrocyclic Acyl Guanidines as Beta-Secretase Inhibitors
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There is provided a series of heterocyclic-containing macrocyclic acyl guanidines of Formula (I) or a stereoisomer; or a nontoxic pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5,
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Page/Page column 6
(2008/12/04)
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- N-Aryl Pyrrolidine Derivatives as Beta-Secretase Inhibitors
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There is provided a series of substituted N-aryl pyrrolidine derivatives of Formula (I) or a stereoisomer; or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R5′, R6, R7, and p as defined herein, their pharmaceutical compositions and methods of use. These compounds inhibit the processing of amyloid precursor protein (APP) by β-secretase and, more specifically, inhibit the production of Aβ-peptide. The present disclosure is directed to compounds useful in the treatment of neurological disorders related to β-amyloid production, such as Alzheimer's disease and other conditions affected by anti-amyloid activity.
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Page/Page column 8-9
(2010/11/28)
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- Indole acetic acid acyl guanidines as beta-secretase inhibitors
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There is provided a series of substituted acyl guanidines of Formula (I) or a stereoisomer; or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, and
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Page/Page column 12
(2008/06/13)
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- Oxime-Containing Acyl Guanidines as Beta-Secretase Inhibitors
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There is provided a series of substituted oxime-containing acyl guanidines of Formula (I) or a stereoisomer; or a nontoxic pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6
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Page/Page column 7
(2010/11/28)
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- Serine protease inhibitors
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PCT No. PCT/EP97/00625 Sec. 371 Date Aug. 12, 1998 Sec. 102(e) Date Aug. 12, 1998 PCT Filed Feb. 11, 1997 PCT Pub. No. WO97/30073 PCT Pub. Date Aug. 21, 1997The invention relates to a compound having formula (I), wherein A, B, X, N, Z and Q are defined as
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