- Annular tautomerism of 3(5)-disubstituted-1H-pyrazoles with ester and amide groups
-
A series of disubstituted 1H-pyrazoles with methyl (1), amino (2), and nitro (3) groups, as well as ester (a) or amide (b) groups in positions 3 and 5 was synthesized, and annular tautomerism was investigated using X-ray, theoretical calculations, NMR, and FT-IR methods. The X-ray experiment in the crystal state showed for the compounds with methyl (1a, 1b) and amino (2b) groups the tautomer with ester or amide groups at position 3 (tautomer 3), but for those with a nitro group (3b, 4), tautomer 5. Similar results were obtained in solution by NMR NOE experiments in CDCl3, DMSO-d6, and CD3OD solvents. However, tautomer equilibrium was observed for 2b in DMSO. The FT-IR spectra in chloroform and acetonitrile showed equilibria, which can be ascribed to conformational changes of the cis/trans arrangement of the ester/amide group and pyrazole ring. Theoretical analysis using the M06-2X/6-311++G(d,p) method (in vacuo, chloroform, acetonitrile, and water) and measurement of aromaticity (NICS) showed dependence on internal hydrogen bonds, the influence of the environment, and the effect of the substituent. These factors, pyrazole aromaticity and intra- and inter-molecular interactions, seem to have a considerable influence on the choice of tautomer.
- Kusakiewicz-Dawid, Anna,Porada, Monika,Dziuk, B?azej,Siod?ak, Dawid
-
-
Read Online
- FUSED RING PYRIMIDONE DERIVATIVES FOR USE IN THE TREATMENT OF HBV INFECTION OR OF HBV-INDUCED DISEASES
-
Provided are compounds according to any of Formula (I-1) to (I-7), pharmaceutical compositions comprising at least one of said compounds, their use as a medicament, and their use in treating chronic hepatitis B virus (HBV) infection. Methods for preparing compounds according to any of Formula (I-1) to (I-7) are also provided.
- -
-
Page/Page column 201; 219
(2022/04/03)
-
- Discovery of Aminopyrazole Derivatives as Potent Inhibitors of Wild-Type and Gatekeeper Mutant FGFR2 and 3
-
Fibroblast growth factor receptors (FGFR) 2 and 3 have been established as drivers of numerous types of cancer with multiple drugs approved or entering late stage clinical trials. A limitation of current inhibitors is vulnerability to gatekeeper resistance mutations. Using a combination of targeted high-throughput screening and structure-based drug design, we have developed a series of aminopyrazole based FGFR inhibitors that covalently target a cysteine residue on the P-loop of the kinase. The inhibitors show excellent activity against the wild-type and gatekeeper mutant versions of the enzymes. Further optimization using SAR analysis and structure-based drug design led to analogues with improved potency and drug metabolism and pharmacokinetics properties.
- Brawn, Ryan A.,Cook, Andrew,Omoto, Kiyoyuki,Ke, Jiyuan,Karr, Craig,Colombo, Federico,Virrankoski, Milena,Prajapati, Sudeep,Reynolds, Dominic,Bolduc, David M.,Nguyen, Tuong-Vi,Gee, Patricia,Borrelli, Deanna,Caleb, Benjamin,Yao, Shihua,Irwin, Sean,Larsen, Nicholas A.,Selvaraj, Anand,Zhao, Xuesong,Ioannidis, Stephanos
-
supporting information
p. 93 - 98
(2020/12/21)
-
- SELECTIVE FOXO INHIBITORS FOR TREATMENT OF DIABETES AND OTHER DISORDERS RELATED TO IMPAIRED PANCREATIC FUNCTION
-
Various embodiments relate to a compound (represented by Formula I) or a pharmaceutically acceptable salt or tautomer thereof. The compound may selectively inhibit a Forkhead Box O1 (FOXO1) transcription factor. Various embodiments relate to methods compr
- -
-
Paragraph 0121-0122
(2020/10/18)
-
- APELIN RECEPTOR AGONISTS AND METHODS OF USE THEREOF
-
Provided herein are agonists of the apelin receptor for the treatment of disease. The compounds disclosed herein are useful for the treatment of a range of cardiovascular, renal and metabolic conditions.
- -
-
Paragraph 0563-0565
(2019/02/25)
-
- HETEROCYCLIC COMPOUNDS AS PRMT5 INHIBITORS
-
The compounds of Formula I, Formula Ia, and Formula Ib are described herein along with their analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts, pharmaceutical compositions, metabolites, and prodrugs thereof. These compounds inhibit PRMT5 and are useful as therpeautic or ameliorating agent for diseases that are involved in cellular growth such as malignant tumors, schizophrenia, Alzheimer's disease, Parkinson's disease and the like.
- -
-
Paragraph 000213
(2019/06/11)
-
- HETEROAROMATIC DERIVATIVES AS NIK INHIBITORS
-
The present invention relates to pharmaceutical agents useful for therapy and/or prophylaxis in a mammal, and in particular to inhibitors of NF-κB-inducing kinase (NIK - also known as MAP3K14) useful for treating diseases such as cancer, inflammatory disorders, metabolic disorders and autoimmune disorders. The invention is also directed to pharmaceutical compositions comprising such compounds, and to the use of such compounds or pharmaceutical compositions for the prevention or treatment of diseases such as cancer, inflammatory disorders, metabolic disorders including obesity and diabetes, and autoimmune disorders.
- -
-
Page/Page column 317; 318
(2018/02/03)
-
- CHEMICAL COMPOUNDS AS INHIBITORS OF INTERLEUKIN-1 ACTIVITY
-
The present disclosure relates to novel sulfonylurea and sulfonyl thiourea compounds and related compounds and their use in treating a disease or condition responsive to modulation of cytokines such as IL-1β and IL-18, modulation of NLRP3 or inhibition of the activation of NLRP3 or related components of the inflammatory process.
- -
-
Paragraph 001030; 001031; 001032
(2018/08/12)
-
- PHOSPHONATE COMPOUNDS FOR TREATMENT OF MEDICAL DISORDERS
-
Compounds, methods of use, and processes for making inhibitors of complement Factor D comprising Formula (I), or a pharmaceutically acceptable salt or composition thereof wherein R12 or R13 on the A group is a phosphonate substituent (R32) are provided. The inhibitors described herein target Factor D and inhibit or regulate the complement cascade. The inhibitors of Factor D described herein reduces the excessive activation of complement.
- -
-
Paragraph 0461; 0580
(2017/03/14)
-
- ARYL, HETEROARYL, AND HETEROCYCLIC COMPOUNDS FOR TREATMENT OF MEDICAL DISORDERS
-
Compounds, methods of use, and processes for making inhibitors of complement Factor D comprising Formula I, or a pharmaceutically acceptable salt or composition thereof wherein R12 or R13 on the A group is an aryl, heteroaryl or heterocycle (R32) are provided. The inhibitors of Factor D described herein reduce the excessive activation of complement.
- -
-
Paragraph 0727
(2017/03/14)
-
- PHOSPHONATE COMPOUNDS FOR TREATMENT OF IMMUNE AND INFLAMMATORY DISORDERS
-
Compounds, methods of use, and processes for making inhibitors of complement Factor D are provided comprising Formula I, I" and I''' or a pharmaceutically acceptable salt or composition thereof. The inhibitors described herein target Factor D and inhibit
- -
-
Paragraph 0618
(2017/03/14)
-
- ARYL, HETEROARYL, AND HETEROCYCLIC COMPOUNDS FOR TREATMENT OF IMMUNE AND INFLAMMATORY DISORDERS
-
Compounds, methods of use, and processes for making inhibitors of complement Factor D are provided comprising Formula I, I" and I'" or a pharmaceutically acceptable salt or composition thereof. The inhibitors described herein target Factor D and inhibit or regulate the complement cascade. The inhibitors of Factor D described herein reduces the excessive activation of complement.
- -
-
Paragraph 0663
(2017/03/14)
-
- COMPOUNDS FOR THE TREATMENT OF MEDICAL DISORDERS
-
Compounds, methods of use, and processes for making inhibitors of complement Factor D comprising Formula (I), or a pharmaceutically acceptable salt or composition thereof The inhibitors described herein target Factor D and inhibit or regulate the complement cascade. The inhibitors of Factor D described herein reduce the excessive activation of complement.
- -
-
Paragraph 0565
(2017/03/14)
-
- NOVEL COMPOUNDS
-
The present invention relates to novel compounds and methods for the manufacture of inhibitors of deubiquitylating enzymes (DUBs). In particular, the invention relates to the inhibition of ubiquitin C-terminal hydrolase L1 (UCHL1). The invention further relates to the use of DUB inhibitors in the treatment of cancer and other indications. Compounds of the invention include compounds having the formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 to R8 are as defined herein.
- -
-
Page/Page column 170-171
(2016/04/20)
-
- HETEROCYCLIC MODULATORS OF LIPID SYNTHESIS AND COMBINATIONS THEREOF
-
Heterocyclic modulators of lipid synthesis are provided as well as pharmaceutically acceptable salts thereof; pharmaceutical compositions comprising such compounds; and methods of treating conditions characterized by disregulation of a fatty acid synthase pathway by the administration of such compounds and combinations of such compounds and other therapeutic agents.
- -
-
Page/Page column 305
(2015/07/07)
-
- HETEROCYCLIC BTK INHIBIT ORS
-
The invention provides compounds of Formula (I). Pharmaceutically acceptable salts, pro-drugs, biologically active metabolites, stereoisomers and isomers thereof wherein the variable are de fined he E in. The compounds of the invention are useful for treating immunologic al and oncological conditions.
- -
-
Page/Page column 49
(2015/11/09)
-
- SUBSTITUTED PYRIMIDINE COMPOUNDS, COMPOSITIONS AND MEDICINAL APPLICATIONS THEREOF
-
The present disclosure relates to pyrimidine compounds of formula (I), their stereoisomers, tautomers, pharmaceutically acceptable salts, polymorphs, solvates, and hydrates thereof. The present disclosure also relates to process of preparation of these pyrimidine compounds, and to pharmaceutical compositions containing them. The compounds of the present disclosure are useful in the treatment, prevention or suppression of diseases and disorders mediated by epidermal growth factor receptor (EGFR) family kinases.
- -
-
Paragraph 00084
(2015/03/13)
-
- Discovery of triazolone derivatives as novel, potent stearoyl-CoA desaturase-1 (SCD1) inhibitors
-
Stearoyl-CoA desaturase-1 (SCD1) plays an important role in lipid metabolism. Inhibition of SCD1 activity represents a potential novel approach for the treatment of metabolic diseases such as obesity, type 2 diabetes and dyslipidemia, as well as skin diseases, acne and cancer. Herein, we report the synthesis and structure-activity relationships (SAR) of a series of novel triazolone derivatives, culminating in the identification of pyrazolyltriazolone 17a, a potent SCD1 inhibitor, which reduced plasma C16:1/C16:0 triglycerides desaturation index (DI) in an acute Lewis rat model in a dose dependent manner, with an ED50 of 4.6 mg/kg. In preliminary safety studies, compound 17a did not demonstrate adverse effects related to SCD1 inhibition after repeat dosing at 100 mg/kg. Together, these data suggest that sufficient safety margins can be achieved with certain SCD1 inhibitors, thus allowing exploration of clinical utility in metabolic disease settings.
- Sun, Shaoyi,Zhang, Zaihui,Pokrovskaia, Natalia,Chowdhury, Sultan,Jia, Qi,Chang, Elaine,Khakh, Kuldip,Kwan, Rainbow,McLaren, David G.,Radomski, Chris C.,Ratkay, Leslie G.,Fu, Jianmin,Dales, Natalie A.,Winther, Michael D.
-
p. 455 - 465
(2015/01/30)
-
- Novel tricyclic pyrazolopyrimidines as potent and selective GPR119 agonists
-
Systematic SAR optimization of the GPR119 agonist lead 1, derived from an internal HTS campaign, led to compound 29. Compound 29 displays significantly improved in vitro activity and oral exposure, leading to GLP1 elevation in acutely dosed mice and reduc
- Azimioara, Mihai,Alper, Phil,Cow, Christopher,Mutnick, Daniel,Nikulin, Victor,Lelais, Gerald,Mecom, John,McNeill, Matthew,Michellys, Pierre-Yves,Wang, Zhiliang,Reding, Esther,Paliotti, Michael,Li, Jing,Bao, Dingjiu,Zoll, Jocelyn,Kim, Young,Zimmerman, Matthew,Groessl, Todd,Tuntland, Tove,Joseph, Sean B.,McNamara, Peter,Seidel, H. Martin,Epple, Robert
-
supporting information
p. 5478 - 5483
(2015/01/09)
-
- INHIBITORS OF BRUTON'S TYROSINE KINASE
-
This application discloses the Btk inhibitor compounds 6-tert-Butyl-8-fluoro-2-{3- hydroxymethyl-4-[1-methyl-5-(1'-methyl-1',2',3',4',5',6'-hexahydro-[3,4']bipyridinyl-6-ylamino)- 6-oxo-1,6-dihydro-pyridazin-3-yl]-pyridin-2-yl}-2H-phthalazin-1-one, 2-(2-{3-[5-(5-Azetidin-1- ylmethyl-1-methyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-2- hydroxymethyl-phenyl}-8-fluoro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-methyl-propionitrile, and 6-tert-Butyl-2-[2-hydroxymethyl-3-(5-{5-[(2-methoxy-ethylamino)-methyl]-pyridin-2- ylamino}-6-oxo-1,6-dihydro-pyridin-3-yl)-phenyl]-3,4-dihydro-2H-isoquinolin-1-one, formulations thereof, and methods of treatment of asthma, as described herein.
- -
-
Page/Page column 27; 63-64
(2014/06/23)
-
- HISTONE DEACETYLASE INHIBITORS AND COMPOSITIONS AND METHODS OF USE THEREOF
-
Provided are certain histone deacetylase (HDAC) inhibitors of Formula I, compositions thereof, and methods of their use.
- -
-
Paragraph 00198
(2014/10/15)
-
- INHIBITORS OF BRUTON'S TYROSINE KINASE
-
This application discloses compounds according to generic Formula I: wherein the variables are defined as described herein, and which inhibit Btk. The compounds disclosed herein are useful to modulate the activity of Btk and treat diseases associated with
- -
-
Page/Page column 89
(2013/03/26)
-
- Inhibitors of Bruton's Tyrosine Kinase
-
This application discloses 6-(2-Hydroxymethyl-phenyl)-2-methyl-2H-pyridazin-3-one derivatives according to generic Formula I: wherein, variables X, R, and Y4, are defined as described herein, which inhibit Btk. The compounds disclosed herein are useful to modulate the activity of Btk and treat diseases associated with excessive Btk activity. The compounds are further useful to treat inflammatory and auto immune diseases associated with aberrant B-cell proliferation, such as rheumatoid arthritis. Also disclosed are compositions containing compounds of Formula I and at least one carrier, diluent or excipient.
- -
-
Page/Page column 118
(2012/03/08)
-
- PYRAZOLE DERIVATIVES WHICH MODULATE STEAROYL-COA DESATURASE
-
The present invention provides heterocyclic derivatives that modulate the activity of stearoyl-CoA desaturase. Methods of using such derivatives to modulate the activity of stearoyl-CoA desaturase and pharmaceutical compositions comprising such derivative
- -
-
Page/Page column 68
(2011/04/25)
-
- PYRIDAZINONES AND THEIR USE AS BTK INHIBITORS
-
Compounds of Formula (I) that inhibit Btk are described herein. Pharmaceutical compositions comprising at least one compound of Formula (I), together with at least one pharmaceutically acceptable vehicle chosen from carriers, adjuvants, and excipients, ar
- -
-
Page/Page column 205
(2010/06/15)
-
- Nitropyrazoles : 118. Synthesis and transformations of 5-amino-3,4- dinitropyrazole
-
A method of preparation of 5-amino-3,4-dinitropyrazole (1) from 3(5)-methyl-5(3)-nitro- and 3(5)-methyl-4,5(3)-dinitropyrazoles was developed, the key step of which was the Hofmann rearrengement of nitro- and dinitropyrazolecarboxamides. The protonation o
- Dalinger,Vatsadse,Shkineva,Popova,Ugrak,Shevelev
-
experimental part
p. 1631 - 1638
(2011/05/03)
-
- FUSED PYRIMIDINES
-
Compounds of formula (I), or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer, wherein ring B and the pyrimidine to which it is fused, R4, R5, R6, R7, m and n have the meanings as given in the description and the claims, which are effective inhibitors of the Pi3K/Akt pathway, processes for their production and their use as pharmaceuticals.
- -
-
Page/Page column 144
(2010/09/03)
-
- Susceptibility of methyl 3-Amino-1H-pyrazole-5-carboxylate to acylation
-
In the search for a new method of synthesis of hybrid peptides with aminopyrazole carboxylic acid, we tried to force selective acylation at the aromatic amino group instead of at the ring nitrogen atom with fairly gentle acylating agents. The acylating agents used were acid anhydrides: acetic anhydride, tert-butyl pyrocarbonate, and 2-(2-methoxyethoxy)ethoxyacetic acid/dicyclohexylcarbodiimide. We succceded in acylation at this amino group with almost none at the ring nitrogen atom. Sometimes, however, acylation in small quantities at the ring nitrogen atom was observed as a by-product. To remove this by-product, imidazole was used. Thus, we were able to obtain the hybrid peptides in question with no protection and subsequent removal required. We synthesized a few these free peptides with no protection of the pyrazole ring. This is a simpler method than that being used currently.
- Kusakiewicz-Dawid, Anna,Gorecki, Lukasz,Masiukiewicz, Elzbieta,Rzeszotarska, Barbara
-
experimental part
p. 4122 - 4132
(2009/12/24)
-
- FUSED BICYCLIC PYRIMIDINES
-
Compounds of formula (I), a tautomer or stereoisomer thereof, or a salt thereof, wherein ring B and the pyrimidine to which it is fused, R4, R5, R6 and R7 have the meanings as given in the description and the claims, are effective inhibitors of the Pi3K/Akt pathway.
- -
-
Page/Page column 106
(2009/04/25)
-
- FUSED BICYCLIC PYRIMIDINES
-
Compounds of formula (I) a tautomer or stereoisomer thereof, or a salt thereof, wherein ring B and the pyrimidine to which it is fused, R4, R5, R6 and R7 have the meanings as given in the description and the claims, are effective inhibitors of the Pi3K/Akt pathway.
- -
-
Page/Page column 41
(2009/06/27)
-
- PYRAZOLOPYRIMIDINES, A PROCESS FOR THEIR PREPARATION AND THEIR USE OF MEDICINE
-
Substituted pyrazolopyrimidine derivatives of formula (I) wherein R1 represents chloro or bromo; R2, R3, R4, R5, R6 and R7 independently represent e.g. hydrogen or C1-6-alkyl; R8 represents a radical R9 or a radical R10, whereby one of the two radicals R8 represents R9 and the other radical R8 represents Ret; R9 represents e.g. a phenyl or thiophene group, and R10 represents e.g. hydrogen or methyl; are potent mGluR5 modulators and are useful for the prevention of acute and chronic neurological disorders.
- -
-
Page/Page column 20
(2008/06/13)
-
- Heterocyclic Derivatives for the Treatment of Diseases Mediated by Stearoyl-Coa Desaturase Enzymes
-
Methods of treating an SCD-mediated disease or condition in a mammal, preferably a human, are disclosed, wherein the methods comprise administering to a mammal in need thereof a compound of formula (I): where x, y, G, J, K, L, M, W, V, R2, R3, R5, R5a, R6, R6a, R7, R7a, R8 and R8a are defined herein. Pharmaceutical compositions comprising the compounds of formula (I) are also disclosed.
- -
-
Page/Page column 22
(2008/12/04)
-
- NOVEL COMPOUNDS FOR THE TREATMENT OF DISEASES ASSOCIATED WITH AMYLOID OR AMYLOID-LIKE PROTEINS
-
The present invention relates to novel compounds that can be employed in the treatment of a group of disorders and abnormalities associated with amyloid protein, such as Alzheimer's disease, and of diseases or conditions associated with amyloid-like proteins. The compounds of the present invention can also be used in the treatment of ocular diseases associated with pathological abnormalities/changes in the tissues of the visual system. The present invention further relates to pharmaceutical compositions comprising these compounds and to the use of these compounds for the preparation of medicaments for treating or preventing diseases or conditions associated with amyloid and/or amyloid-like proteins. A method of treating or preventing diseases or conditions associated with amyloid and/or amyloid-like proteins is also disclosed.
- -
-
Page/Page column 88
(2008/12/05)
-
- HETEROBICYCLIC METALLOPROTEASE INHIBITORS
-
The present invention relates generally to heterobicyclic containing pharmaceutical agents, and in particular, to heterobicyclic metalloprotease inhibitor compounds. More particularly, the present invention provides a new class of heterobicyclic metalloprotease inhibiting compounds that exhibit an increased potency in relation to currently known metalloprotease inhibitors.
- -
-
Page/Page column 165
(2008/12/05)
-
- PYRROLOTRIAZINE KINASE INHIBITORS
-
The present invention provides compounds of formula I and pharmaceutically acceptable salts thereof. The formula I compounds inhibit tyrosine kinase activity of such as TrkA, TrkB, TrkC, Jak2, Jak3 and CK2, thereby making them useful as antiproliferative agents for the treatment of cancer and other diseases.
- -
-
Page/Page column 43
(2008/06/13)
-
- Preparation and optimization of a series of 3-carboxamido-5- phenacylaminopyrazole bradykinin B1 receptor antagonists
-
The B1 receptor is an attractive target for the treatment of pain and inflammation. A series of 3-carboxamido-5-phenacylamino pyrazole B1 receptor antagonists are described that exhibit good potency against B1 and high selectivity over B2. Initially, N-un
- Dressen, Darren,Garofalo, Albert W.,Hawkinson, Jon,Hom, Dennis,Jagodzinski, Jacek,Marugg, Jennifer L.,Neitzel, Martin L.,Pleiss, Michael A.,Szoke, Balazs,Tung, Jay S.,Wone, David W. G.,Wu, Jing,Zhang, Heather
-
p. 5161 - 5167
(2008/03/12)
-
- QUINOLINE DERIVATIVES
-
The invention concerns quinoline derivatives of Formula (I): or a pharmaceutically-acceptable salt thereof, wherein each of X1, p, R1, q, R2, R3, R4, R5, Ring A, r and R6 has any of the meanings defined hereinbefore in the description; processes for their preparation, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use in the treatment of cell proliferative disorders.
- -
-
Page/Page column 115
(2008/06/13)
-
- SUBSTITUTED 5-CARBOXYAMIDE PYRAZOLES AND [1,2,4]TRIAZOLES AS ANTIVIRAL AGENTS
-
The present invention provides compounds of formula I wherein X, Y, R1-R7 are as defined herein. Compositions containing these compounds, and methods for inhibiting HCV RNA-dependent RNA polymerase and treating hepatitis C and related disorders using thes
- -
-
Page/Page column 60
(2008/06/13)
-
- BIARYL SUBSTITUTED PYRAZOLES AS SODIUM CHANNEL BLOCKERS
-
Biaryl substituted pyrazole compounds are sodium channel blockers useful for the treatment of pain and other conditions. Pharmaceutical compositions comprise an effective amount of the instant compounds, either alone, or in combination with one or more th
- -
-
-
- 4- BROMO - 5 - (2- CHLORO - BENZOYLAMINO) - 1H - PYRAZOLE - 3 - CARBOXYLIC ACID AMIDE DERIVATIVES AND RELATED COMPOUNDS AS BRADYKININ B1 RECEPTOR ANTAGONISTS FOR THE TREATMENT OF INFLAMMATORY DISEASES
-
Disclosed are compounds of formula I and II that are bradykinin B1 receptor antagonists and are useful for treating diseases, or relieving adverse symptoms associated with disease conditions, in mammals mediated by bradykinin B1 receptor. Certain of the compounds exhibit increased potency and are also expected to exhibit increased duration of action.
- -
-
-
- New heterocyclic β-sheet ligands with peptidic recognition elements
-
A detailed and comprehensive overview is presented about the design, modeling, and synthesis, as well as spectroscopic characterization, of a new class of β-sheet ligands. The characteristic feature of these compounds is a peptidic chimeric structure formed from a specific combination of aminopyrazolecarboxylic acids with naturally occurring α-amino acids. These hybrid peptides are designed with the aid of molecular modeling to exist mainly in an extended conformation. All their hydrogen bond donors and acceptors can be aligned at the bottom face in such a way that a perfect complementarity toward β-sheets is obtained. Thus the aminopyrazoles impart rigidity and a highly efficient DAD sequence for the recognition of whole dipeptide fragments, whereas the natural α-amino acids are designed to mimick recognition sites in proteins, ultimately leading to sequence-selective protein recognition. The synthetic protocols either rely upon solution phase peptide coupling with a PMB protecting group strategy or solid-phase peptide coupling based on the Fmoc strategy, using the same protecting group. In solution, a key building block was prepared by catalytic reduction of a nitropyrazolecarboxylic acid precursor. Subsequently, it was (N-1)-protected with a PMB group, and elongated by HCTU- or T3P-assisted peptide coupling with dipeptide fragments, followed by PyClop-assisted coupling with another nitropyrazolecarboxylic acid building block. Final simultaneous deprotection of all PMB groups with hot TFA completed the high-yield protocol, which works racemization-free. After preparing a similar key building block with an Fmoc protection at N-3, we developed a strategy suitable for automated synthesis of larger hybrid ligands on a peptide synthesizer. Attachment of the first amino acid to a polystyrene resin over the Sieber amide linker is followed by an iterative sequence consisting of Fmoc deprotection with piperidine and subsequent coupling with natural α-amino acid via HATU/HOAt. High yields of free hybrid peptides are obtained after mild acidic cleavage from the resin, followed by deprotection of the PMB groups with hot TFA. The new aminopyrazole peptide hybrid compounds were characterized by various spectroscopic measurements including CD spectra, VT, and ROESY NMR experiments. All these accumulated data indicate the absence of any intramolecular hydrogen bonds and strongly support an extended conformation in solution, ideal for docking on to solvent-exposed β-sheets in proteins. Initial results from aggregation tests of pathological proteins with these and related ligands look extremely promising.
- Rzepecki,Gallmeier,Geib,Cernovska, Katarina,Koenig,Schrader
-
p. 5168 - 5178
(2007/10/03)
-
- PYRAZOLO` 1,5A! PYRIMIDINE COMPOUNDS AS ANTIVIRAL AGENTS
-
The invention relates to the inhibition of hepatitis C virus (HCV) replication. In particular, embodiments of the invention provide compounds and methods for inhibiting HCV RNA-dependent RNA polymerase enzymatic activity. The invention also provides compositions and methods for the prophylaxis and treatment of HCV infection.
- -
-
-