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ABSTRACT: Metal-catalyzed reactions of ynimides with alcohols to afford β-ketoimides and oxazoles are demonstrated. The triple bond of ynamides is generally activated by mineral acids or metal salts to lead to the regioselective addition of nucleophiles at the α-C-atom, because of the inherent electronic bias. In contrast, the two neighboring carbonyl groups of ynimides decrease the electron density of the triple bond and the nucleophiles attack the carbonyl C-atom.
Organic Letters 03/2013; · 5.86 Impact Factor
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ABSTRACT: Plasmin is best known as the key molecule in the fibrinolytic system, which is critical for clot lysis and can initiate matrix metalloproteinase (MMP) activation cascade. Along with MMP, plasmin is suggested to be involved in physiological processes that are linked to the risk of carcinoma formation. Plasmin inhibitors could be perceived as a promising new principle in the treatment of diseases triggered by plasmin. On the basis of the peptidic sequence derived from the synthetic plasmin substrate, a series of peptidic plasmin inhibitors possessing nitrile as warhead were prepared and evaluated for their inhibitory activities against plasmin and other serine proteases, plasma kallikrein and urokinase. The most potent peptidic inhibitors with the nitrile warhead exhibit the potency toward plasmin (IC(50) = 7.7-11 μM) and are characterized by their selectivity profile against plasma kallikrein and urokinase. The results and molecular modeling of the peptidic inhibitor complexed with plasmin reveal that the P2 residue makes favorable contacts with the open binding pocket comprising the S2 and S3 subsites of plasmin. Copyright © 2012 European Peptide Society and John Wiley & Sons, Ltd.
Journal of Peptide Science 09/2012; 18(10):620-5. · 1.80 Impact Factor
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ABSTRACT: Plasmin plays important roles in various physiological systems. The identification of inhibitors controlling its regulation represents a promising drug-discovery challenge. To develop selective inhibitors of plasmin, structural information of the binding modes is crucial. Here, a computational docking study was conducted to provide structural insight into plasmin subsite interactions with substrates/inhibitors. Predicted binding modes of two peptide-substrates (D/L-Ile-Phe-Lys), and potent and weak inhibitors (YO-2 and PKSI-527) suggested non-prime and prime subsite interactions relevant to recognition by plasmin. Predicted binding modes also correlated well with the experimental structure-activity relationships for plasmin substrates/inhibitors, namely the differences of K(M) values between the D- and L-peptide-substrates and inhibitory potencies of YO-2 and PKSI-527. In particular, interaction observed at a hydrophobic pocket near S2 and at a tunnel-shaped hydrophobic S1' was strongly suggested to be significantly involved in tight binding of inhibitors to plasmin. Our present findings may aid in the design of potent and selective plasmin inhibitors.
Journal of Enzyme Inhibition and Medicinal Chemistry 10/2011; 27(4):571-7. · 1.62 Impact Factor
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ABSTRACT: Lysine-nitrile derivatives having a trisubstituted benzene, which belongs to a new chemical class, were prepared and tested for inhibitory activities against plasmin and the highly homologous plasma kallikrein and urokinase. The use of the novel chemotype in the development of plasmin inhibitors has been demonstrated by derivatives of compound 9.
Bioorganic & medicinal chemistry letters 09/2011; 21(21):6305-9. · 2.65 Impact Factor
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ABSTRACT: This study describes the first reliable synthesis of N-alkynyl imides (ynimides). This was accomplished with a copper-catalyzed coupling reaction between alkynyl(triaryl)bismuthonium salts and five-membered imides. We also found that it was possible to utilize N-ethynyl phthalimide as a variant of the highly labile ethynamine. 4-Amino-1,2,3-triazole was successfully obtained via the CuAAC reaction of N-ethynyl phthalimide with azide followed by hydrazinolysis of the phthaloyl protecting group.
Organic Letters 06/2011; 13(15):3996-9. · 5.86 Impact Factor
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ABSTRACT: The catalytic site of cathepsin cysteine proteases is located within the binding region which has subsites for substrate amino acids in both the N- and C-terminal direction from the scissile bond. The catalytic site is highly conserved and formed by three residues: Cys, His and Asn. The crucial step of the catalytic process involves formation of a reactive thiolate/imidazolium ion pair, which results from proton transfer between Cys and His, resulting in forming an active Cys residue. In most cases, the development of selective cathepsin inhibitors is moving forward on the basis of: information on the subsites for substrate amino acids, and the warhead which binds to a thiol group of the active center of cathepsins. The various reversible or irreversible cathepsin inhibitors, which were designed over the past 15 years, underscore the importance of inactivation of the cathepsins which are involved in particular diseases. In this special issue of Current Topics in Medicinal Chemistry with the title “The Medicinal Chemistry of the Cathepsin Cysteine Proteases”, the authors provide refined reviews that give a critical update on the current understanding and advance of the medicinal chemistry on the selective cathepsins C, S and K inhibitors developed by many institutes. The human cysteine cathepsin family comprises 11 genes (cathepsins B, C, H, F, K, L, O, S, V, W, and X/Z). Since some of cathepsins are implicated in many physiological processes such as protein degradation, antigen presentation, bone resorption, we now understand how important a role of cathepsins play. Additionally, it has been found that some cathepsins are involved in a number of degradative and invasive processes such as arthritis, tumor invasion and metastasis and muscular dystrophy as well. There exists a discrepancy in the physiological processes that arise from the primary, secondary and tertiary structures of each cathepsin. The understanding of tertiary structure of target enzymes has especially provided a wealth of information to help speed up drug discovery research and bring newer and better therapies to the market place. Tomoo elaborates recent advances in structure of cathepsins B, K, L and S, and also provides a thorough overview of structural features of cathepsins and his approach in structure-based design of cathepsin B specific inhibitors. Like other cysteine proteases cathepsin C is involved in intracellular protein degradation even though the enzyme is the noted exception, existing as an oligomeric enzyme with a molecular weight of 200kDa. Cathepsin C is the physiological activator of groups of serine proteases within immune and inflammatory cells that are vital for the defense of an organism. Percival et al. discuss the therapeutic utility and recent progress in medicinal chemistry of cathepsin C inhibitors. Current marketed therapies for neuropathic pain are based largely on two well established classes: the analgesics opiates and the nonsteroidal anti-inflammatory drugs. Both classes of drugs have limited efficacy and evoke undesirable side effects. The lack of suitable therapies has stimulated research regarding target identification for neuropathic pain. It has been reported that the mRNA encoding cathepsin S was up-regulated in rat dorsal root ganglia following peripheral nerve injury. Cathepsin S is expressed in professional antigen presentation cells such as dendritic cells, B lymphocytes, and macrophages. Hence, the major role of cathepsin S in these cells is in the important proteolytic events that lead to antigen presentation. Cathepsin S inhibitors are thus being developed as immunological therapeutic agents. Wiener et al. review the recent advance in the various peptidic and non-peptidic cathepsin S inhibitors using the structure activity relationship both with and without warhead. Since the discovery of the cysteine protease cathepsin K, many studies have shown that this enzyme is of importance in bone resorption. Kometani et al. provide insights into the hurdles in the drug discovery of cathepsin K inhibitors for the treatment of bone resorption. Odanacatib is the most advanced cathepsin K inhibitor for which the phase III study is currently proceeding to treat post-menopausal osteoporosis. Black discusses the design of Odanacatib and peptidic and non-peptidic analogs derived from Odanacatib. Teno et al. review small molecule non-peptidic inhibitors possessing pyrrolopyrimidine as a new scaffold for cathepsin K.
Current Topics in Medicinal Chemistry 04/2010; 10(7):695-695. · 4.17 Impact Factor
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ABSTRACT: Importance of the field: Bones play many roles in the body, providing structure, protecting organs, anchoring muscles and storing calcium. Over 100 million people worldwide suffer from bone diseases, mainly osteoporosis, cancer-related bone loss, osteoarthritis and inflammatory arthritis. Osteoporosis itself has no specific symptoms, and the main consequence is the increased risk of bone fractures. Therefore, the prevention of bone diseases is important to maintain the quality of life in the human society. However, treatment options are still insufficient. Areas covered in this review: This review article gives a summary of the low molecular mass modulators of bone diseases targets disclosed in patent applications and articles, mainly during the last 5 years. What the reader will gain: Readers will rapidly gain an overview of these modulators not only for historical targets, but also of emerging and re-visited targets. Readers will also be able to see the current research trend and the main players in this field. Take home message: Drug discovery for bone diseases has made progress in the last years. The research area has dynamically shifted from historical targets (bisphosphonate, parathyroid hormone and calcitonin) to newly confirmed targets or targets re-visited which were biologically validated in the past. Cathepsin K inhibitors should be very close to launching in the market.
Expert Opinion on Therapeutic Patents 04/2010; 20(4):563-82. · 3.57 Impact Factor
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ABSTRACT: The recent emergence of osteoporosis as a major health threat in people of advanced age has intensified the search for novel and effective pharmacologic treatments. Given that bone resorption is exceeding bone formation, a reduction in bone mass leads to disease conditions including post-menopausal osteoporosis and tumor-induced osteolysis. Our efforts in this area have focused on the optimization of non-peptidic cathepsin K inhibitors for affinity and selectivity, from an heteroaromatic nitrile as a novel scaffold. This approach has resulted in the discovery of the potent and selective cathepsin K inhibitor, 44. The concentration of cathepsin K inhibitors, including compound 44, in the target tissues such as bone marrow cavity, were predictive parameters for antibone resorptive efficacy in vivo in the rat. The high level of distribution to the bone marrow was also observed for compounds containing pyrrolopyrimidines with novel spiro-structures as the P3 moiety. In a monkey study with the representative inhibitor 44, the antibone resorptive efficacy was detected 8 h after the compound administration. The efficacy persisted throughout the repeated treatment period of 14 days without any evidence for the development of tolerance. This article constitutes a near comprehensive review of the published scientific literature on small molecule non-peptidic inhibitors for cathepsin K developed by Novartis.
Current topics in medicinal chemistry 03/2010; 10(7):752-66. · 4.47 Impact Factor
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Current topics in medicinal chemistry 01/2010; 10(7):695. · 4.47 Impact Factor
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ABSTRACT: The plasmin substrates, D-Ile-Phe-Lys-pNA (I), 3-MV-Phe-Lys-pNA (II), Ile-Phe-Lys-pNA (III), D-Pro-Phe-Lys-pNA (IV), CP-Phe-Lys-pNA (V) and Pro-Phe-Lys-pNA (VI), were synthesized by the conventional solution method and the kinetic parameters of their amidolysis by plasmin were determined. It was found that the free amino group of the D-amino acid in substrates (I) and (IV) made a contribution to an increment in affinity between the substrate and plasmin.
European Journal of Allergy and Clinical Immunology 01/2009; 27(1):79 - 85. · 1.30 Impact Factor
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Naoki Teno,
Keiichi Masuya,
Takeru Ehara,
Takatoshi Kosaka,
Takahiro Miyake,
Osamu Irie,
Yuko Hitomi,
Naoko Matsuura,
Ichiro Umemura,
Genji Iwasaki,
Hiroaki Fukaya,
Kazuhiro Toriyama,
Noriko Uchiyama,
Kazuhiko Nonomura,
Ikuo Sugiyama,
Motohiko Kometani
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ABSTRACT: On the basis of the pyrrolopyrimidine core structure that was previously discovered, cathepsin K inhibitors having a spiro amine at the P3 have been explored to enhance the target, bone marrow, tissue distribution. Several spiro structures were identified with improved distribution toward bone marrow. The representative inhibitor 7 of this series revealed in vivo reduction in C-terminal telopeptide of type I collagen in rats and monkeys.
Journal of Medicinal Chemistry 10/2008; 51(17):5459-62. · 4.80 Impact Factor
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Osamu Irie,
Takatoshi Kosaka,
Masashi Kishida,
Junichi Sakaki,
Keiichi Masuya,
Kazuhide Konishi,
Fumiaki Yokokawa,
Takeru Ehara,
Atsuko Iwasaki,
Yuki Iwaki, [......],
Takanori Kanazawa,
Keiko Tanabe,
Peter C Hiestand,
Marzia Malcangio,
Alyson J Fox,
Stuart J Bevan,
Mohammed Yaqoob,
Andrew J Culshaw,
Terance W Hart,
Allan Hallett
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ABSTRACT: We describe here orally active and brain-penetrant cathepsin S selective inhibitors, which are virtually devoid of hERG K(+) channel affinity, yet exhibit nanomolar potency against cathepsin S and over 100-fold selectivity to cathepsin L. The new non-peptidic inhibitors are based on a 2-cyanopyrimidine scaffold bearing a spiro[3.5]non-6-yl-methyl amine at the 4-position. The brain-penetrating cathepsin S inhibitors demonstrate potential clinical utility for the treatment of multiple sclerosis and neuropathic pain.
Bioorganic & medicinal chemistry letters 09/2008; 18(19):5280-4. · 2.65 Impact Factor
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Osamu Irie,
Takatoshi Kosaka,
Takeru Ehara,
Fumiaki Yokokawa,
Takanori Kanazawa,
Hajime Hirao,
Astuko Iwasaki,
Junichi Sakaki, Naoki Teno,
Yuko Hitomi, [......],
Keiko Tanabe,
Shinichi Koizumi,
Noriko Uchiyama,
Stuart J Bevan,
Marzia Malcangio,
Clive Gentry,
Alyson J Fox,
Mohammed Yaqoob,
Andrew J Culshaw,
Allan Hallett
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ABSTRACT: Cathepsin S inhibitors are well-known to be an attractive target as immunological therapeutic agents. Recently, our gene expression analysis identified that cathepsin S inhibitors could also be effective for neuropathic pain. Herein, we describe the efficacy of selective cathepsin S inhibitors as antihyperalgesics in a model of neuropathic pain in rats after oral administration.
Journal of Medicinal Chemistry 09/2008; 51(18):5502-5. · 4.80 Impact Factor
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Osamu Irie,
Takeru Ehara,
Atsuko Iwasaki,
Fumiaki Yokokawa,
Junichi Sakaki,
Hajime Hirao,
Takanori Kanazawa, Naoki Teno,
Miyuki Horiuchi,
Ichiro Umemura,
Hiroki Gunji,
Keiichi Masuya,
Yuko Hitomi,
Genji Iwasaki,
Kazuhiko Nonomura,
Keiko Tanabe,
Hiroaki Fukaya,
Takatoshi Kosaka,
Christopher R Snell,
Allan Hallett
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ABSTRACT: Nonpeptidic, selective, and potent cathepsin S inhibitors were derived from an in-house pyrrolopyrimidine cathepsin K inhibitor by modification of the P2 and P3 moieties. The pyrrolopyrimidine-based inhibitors show nanomolar inhibition of cathepsin S with over 100-fold selectivity against other cysteine proteases, including cathepsin K and L. Some of the inhibitors showed cellular activities in mouse splenocytes as well as oral bioavailabilities in rats.
Bioorganic & medicinal chemistry letters 08/2008; 18(14):3959-62. · 2.65 Impact Factor
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ABSTRACT: Cathepsin K is known to play an important role in bone resorption, and it has the P2 specificity for proline. Rat cathepsin K has 88% identity with the human enzyme. However, it has been reported that its enzymatic activity for a Cbz-Leu-Arg-MCA substrate is lower than that of human cathepsin K, and that the rat enzyme is not well inhibited by human cathepsin K inhibitors. For this study, we prepared recombinant enzyme to investigate the substrate specificity of rat cathepsin K. Cleavage experiments using the fragment of type I collagen and peptidic libraries demonstrated that rat cathepsin K preferentially hydrolyses the substrates at the P2 Hyp position. Comparison of the S2 site between rat and human cathepsin K sequences indicated that two S2 residues at Ser134 and Val160 in rat are varied to Ala and Leu, respectively, in the human enzyme. Cleavage experiments using two single mutants, S134A and V160L, and one double mutant, S134A/V160L, of rat cathepsin K showed that all the rat mutants lost the P2 Hyp specificity. The information obtained from our comparative studies on rat and human cathepsin K should make a significant impact on developing specific inhibitors of human cathepsin K since rat is usually used as test species.
Journal of Biochemistry 08/2008; 144(4):499-506. · 2.37 Impact Factor
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ABSTRACT: Cyano pyrimidine acetylene and cyano pyrimidine t-amine, which belong to a new chemical class, were prepared and tested for inhibitory activities against cathepsin K and the highly homologous cathepsins L and S. The use of novel chemotypes in the development of cathepsin K inhibitors has been demonstrated by derivatives of compounds 1 and 8.
Bioorganic & medicinal chemistry letters 05/2008; 18(8):2599-603. · 2.65 Impact Factor
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Naoki Teno,
Takahiro Miyake,
Takeru Ehara,
Osamu Irie,
Junichi Sakaki,
Osamu Ohmori,
Hiroki Gunji,
Naoko Matsuura,
Keiichi Masuya,
Yuko Hitomi, [......],
Keigo Gohda,
Atsuko Iwasaki,
Ichiro Umemura,
Sachiyo Tada,
Motohiko Kometani,
Genji Iwasaki,
Sandra W Cowan-Jacob,
Martin Missbach,
René Lattmann,
Claudia Betschart
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ABSTRACT: Pyrrolopyrimidine, a novel scaffold, allows to adjust interactions within the S3 subsite of cathepsin K. The core intermediate 10 facilitated the P3 optimization and identified highly potent and selective cathepsin K inhibitors 11-20.
Bioorganic & Medicinal Chemistry Letters 12/2007; 17(22):6096-100. · 2.55 Impact Factor
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ABSTRACT: Starting from the purine lead structure 1, a new series of cathepsin K inhibitors based on a pyrimidine scaffold have been explored. Investigations of P3 and P2 substituents based on molecular modeling suggestions resulted in potent cathepsin K inhibitors with an improved selectivity profile over other cathepsins.
Journal of Medicinal Chemistry 03/2007; 50(4):591-4. · 5.25 Impact Factor
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ABSTRACT: Ghrelin, discovered in rat stomach as an endogenous growth hormone secretagogue, is octanoylated at the Ser3 residue. Since this octanoylation is essential for the functions of ghrelin, the enzymes that catalyze acylation for ghrelin biosynthesis and deacylation (deactivation step) must be considered as important regulators. We found that rat stomach homogenate contained ghrelin deacylation activity, and we isolated the active fractions by column chromatography. After sequencing and expressing candidate proteins, the ghrelin deacylation enzyme in the stomach was identified as lysophospholipase I (LysoPLA I). The enzyme properties were examined using recombinant rat LysoPLA I expressed in Escherichia coli. K(m) and V(max) values were determined as 6.5 microM and 2.3 micromol/min/mg for ghrelin and 2.2 x 10(2) microM and 0.5 micromol/min/mg for lysophosphatidylcholine (LysoPC), respectively. The deacylation of both substrates was inhibited by methyl arachidonyl fluorophosphonate (MAFP), which is known as an irreversible inhibitor of LysoPLA I. These results reveal that LysoPLA I catalyzes the removal of n-octanoic acid from ghrelin to form des-acyl ghrelin. Identification of the ghrelin deacylation enzyme in the stomach and a deacylation inhibitor will be helpful in investigating ghrelin biosynthesis.
Biochemical and Biophysical Research Communications 01/2005; 325(4):1487-94. · 2.48 Impact Factor
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ABSTRACT: Human endothelin-1 (ET-1) is a potent cardiovascular bioactive peptide. Its activity is based on the C-terminal residues, e.g., Trp 21 in particular. Recently, we reported an NMR solution structure of ET-1, which has a C-terminal hydrophobic core around Tyr 13. This C-terminal conformation does not agree with a previously reported X-ray crystal structure. To clarify the discrepancy, we performed photo-CIDNP NMR in combination with MALDI-TOF MS. The photo-CIDNP results revealed that the Tyr 13 aromatic ring is concealed in a hydrophobic interaction. MALDI-TOF MS experiments showed this is an intramolecular interaction in monomeric form, which is also supported by sedimentation analysis and two-dimensional NMR cross-peak line shapes. Thus, we confirmed the intramolecular hydrophobic core around Tyr 13 in aqueous solution, which agrees with the solution structure. The C-terminal conformational discrepancy between the solution and crystal was caused by the intermolecular hydrogen bond between Tyr 13 of one molecule and Asp 8 of the other in a dimer-like formation of crystalline ET-1. On the other hand, we indicated that endothelin-3, another isoform of the endothelin, has an apparent self-association equilibrium under the same condition in which three tyrosines participate.
Biochemistry 12/2004; 43(44):13932-6. · 3.42 Impact Factor
