- Synthesis and in vitro antifungal activities of novel triazole antifungal agent CS-758
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Synthesis and in vitro antifungal activities of a novel triazole antifungal agent CS-758 (former name, R120758) are described. The minimum inhibitory concentrations (MICs) of a series of dioxane-triazole compounds related to R-102557 were examined. Variat
- Konosu, Toshiyuki,Oida, Sadao,Nakamura, Yoshie,Seki, Shinobu,Uchida, Takuya,Somada, Atsushi,Mori, Makoto,Harada, Yoshiko,Kamai, Yasuki,Harasaki, Tamako,Fukuoka, Takashi,Ohya, Satoshi,Yasuda, Hiroshi,Shibayama, Takahiro,Inoue, Shin-Ichi,Nakagawa, Akihiko,Seta, Yasuo
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Read Online
- Optimization of Novel 1-Methyl-1 H-Pyrazole-5-carboxamides Leads to High Potency Larval Development Inhibitors of the Barber's Pole Worm
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A phenotypic screen of a diverse library of small molecules for inhibition of the development of larvae of the parasitic nematode Haemonchus contortus led to the identification of a 1-methyl-1H-pyrazole-5-carboxamide derivative with an IC50 of 0.29 μM. Medicinal chemistry optimization targeted modifications on the left-hand side (LHS), middle section, and right-hand side (RHS) of the scaffold in order to elucidate the structure-activity relationship (SAR). Strong SAR allowed for the iterative and directed assembly of a focus set of 64 analogues, from which compound 60 was identified as the most potent compound, inhibiting the development of the fourth larval (L4) stage with an IC50 of 0.01 μM. In contrast, only 18% inhibition of the mammary epithelial cell line MCF10A viability was observed, even at concentrations as high as 50 μM.
- Le, Thuy G.,Kundu, Abhijit,Ghoshal, Atanu,Nguyen, Nghi H.,Preston, Sarah,Jiao, Yaqing,Ruan, Banfeng,Xue, Lian,Huang, Fei,Keiser, Jennifer,Hofmann, Andreas,Chang, Bill C. H.,Garcia-Bustos, Jose,Jabbar, Abdul,Wells, Timothy N. C.,Palmer, Michael J.,Gasser, Robin B.,Baell, Jonathan B.
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p. 10875 - 10894
(2019/01/04)
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- 3-FLUORO-BENZONITRILE INHIBITORS OF 11-BETA-HYDROXYLASE
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The present invention relates to new 3-fluoro-benzonitrile modulators of 11-β- hydroxylase, pharmaceutical compositions thereof, and methods of use thereof.
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Paragraph 00144
(2016/08/03)
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- Pesticidal compositions and processes related thereto
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This document discloses molecules having the following formula (“Formula One”): and processes associated therewith.
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Page/Page column 97; 98
(2016/01/09)
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- PESTICIDAL COMPOSITIONS AND PROCESSES RELATED THERETO
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This document discloses molecules having the following formula ("Formula One"): and processes associated therewith.
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Page/Page column 96; 97
(2014/07/08)
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- PESTICIDAL COMPOSITIONS AND PROCESSES RELATED THERETO
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This document discloses molecules having the following formula (“Formula One”): and processes associated therewith.
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Page/Page column
(2014/06/25)
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- PESTICIDAL COMPOSITIONS AND PROCESSES RELATED THERETO
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This document discloses molecules having the following formula (“Formula One”): and processes associated therewith.
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Paragraph 0470-0471
(2014/06/25)
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- PESTICIDAL COMPOSITIONS AND PROCESSES RELATED THERETO
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This document discloses molecules having the following formula ("Formula One") and processes associated therewith.
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Page/Page column 98
(2014/07/08)
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- Discovery and in vivo evaluation of potent dual CYP11B2 (aldosterone synthase) and CYP11B1 inhibitors
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Aldosterone is a key signaling component of the renin-angiotensin- aldosterone system and as such has been shown to contribute to cardiovascular pathology such as hypertension and heart failure. Aldosterone synthase (CYP11B2) is responsible for the final three steps of aldosterone synthesis and thus is a viable therapeutic target. A series of imidazole derived inhibitors, including clinical candidate 7n, have been identified through design and structure-activity relationship studies both in vitro and in vivo. Compound 7n was also found to be a potent inhibitor of 11β-hydroxylase (CYP11B1), which is responsible for cortisol production. Inhibition of CYP11B1 is being evaluated in the clinic for potential treatment of hypercortisol diseases such as Cushing's syndrome.
- Meredith, Erik L.,Ksander, Gary,Monovich, Lauren G.,Papillon, Julien P. N.,Liu, Qian,Miranda, Karl,Morris, Patrick,Rao, Chang,Burgis, Robin,Capparelli, Michael,Hu, Qi-Ying,Singh, Alok,Rigel, Dean F.,Jeng, Arco Y.,Beil, Michael,Fu, Fumin,Hu, Chii-Whei,Lasala, Daniel
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supporting information
p. 1203 - 1207
(2014/01/06)
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- PESTICIDAL COMPOSITIONS AND PROCESSES RELATED THERETO
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This document discloses molecules having the following formula (“Formula One”): and processes associated therewith.
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Page/Page column 52
(2013/02/28)
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- NOVEL ALPHA-(N-SULFONAMIDO)ACETAMIDE COMPOUNDS INCORPORATING DEUTERIUM AS INHIBITORS OF BETA AMYLOID PEPTIDE PRODUCTION
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The present disclosure provides novel deuterated alpha-(N-sulfonamido)acetamide compounds, their pharmaceutical composition, processes thereof and a method for the treatment of Alzheimer's disease, head trauma, traumatic brain injury, and/or dementia pugilistica and/or other conditions associated with β-amyloid peptide.
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Page/Page column 11
(2010/10/03)
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- CYSTEINE PROTEASE INHIBITORS FOR THE TREATMENT OF PARASITIC DISEASES
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Several parasites responsible for mammalian diseases are dependent on cysteine protease for various life-cycle functions. Inhibition or decreasing function of these proteases can be useful in the treatment and/or prevention of these parasitic diseases including; toxoplasmosis, malaria, African trypanosomiasis, Chagas disease, leishmaniasis, schistosomiasis, amebiasis, giardiasis, clonorchiasis, opisthorchiasis, paragonimiasis, fasciolopsiasis, lymphatic filariasis, onchocerciasis, dracunculiasis, ascariasis, trichuriasis, strongyloidiasis, trichostrongyliasis, trichomoniasis or cestodiasis. Compounds of formula I of the invention are capable of treating and/or preventing the above-identified diseases:
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Page/Page column 41-42
(2009/07/03)
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- Novel Alpha-(N-Sulfonamido)Acetamide Compound as an Inhibitor of Beta Amyloid Peptide Production
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The present invention provides a novel alpha-(N-sulfonamido)acetamide compound, its pharmaceutical composition, processes thereof and a method for the treatment of Alzheimer's disease and other conditions associated with β-amyloid peptide.
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Page/Page column 16-17
(2009/05/28)
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- Design, synthesis, and biological evaluation of pyrazinones containing novel P1 needles as inhibitors of TF/VIIa
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Herein is described the design, synthesis, and enzymatic activity of a series of substituted pyrazinones as inhibitors of the TF/VIIa complex. These inhibitors were designed to explore replacement and variation of the P1 amidine described previously [J. Med. Chem. 2003, 46, 4050]. The P1 needle replacements were selected based upon their reduced basicity compared to the parent phenyl amidine (pKa ～ 12). A contributing factor towards the oral bioavailability of a compound is the ionization state of the compound in the intestinal tract. The desired outcome of the study was to identify an orally bioavailable TF-VIIa inhibitor.
- Trujillo, John I.,Huang, Horng-Chih,Neumann, William L.,Mahoney, Matthew W.,Long, Scott,Huang, Wei,Garland, Danny J.,Kusturin, Carrie,Abbas, Zaheer,South, Michael S.,Reitz, David B.
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p. 4568 - 4574
(2008/02/11)
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- NOVEL OXABISPIDINE COMPOUNDS AND THEIR USE IN THE TREATMENT OF CARDIAC ARRHYTHMIAS
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There is provided compounds of formula (I), wherein R1, R2, R3, R4, R 41 to R46, A, B and G have meanings given in the description, which are useful in the prophylaxis and in the treatment of arrhythmias, in particular atrial and ventricular arrhythmias.
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Page/Page column 93
(2008/06/13)
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- A fluorine scan of the phenylamidinium needle of tricyclic thrombin inhibitors: Effects of fluorine substitution on pKa and binding affinity and evidence for intermolecular C-F...CN interactions
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The H-atoms of the phenylamidinium needle of tricyclic thrombin inhibitors, which interacts with Asp189 at the bottom of the selectivity pocket S1 of the enzyme, were systematically exchanged with F-atoms in an attempt to improve the pharmacokinetic prope
- Olsen, Jacob,Seiler, Paul,Wagner, Bjoern,Fischer, Holger,Tschopp, Thomas,Obst-Sander, Ulrike,Banner, David W.,Kansy, Manfred,Mueller, Klaus,Diederich, Francois
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p. 1339 - 1352
(2007/10/03)
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- Efficacious and orally bioavailable thrombin inhibitors based on a 2,5-thienylamidine at the P1 position: Discovery of N-carboxymethyl-D-diphenylalanyl-L-prolyl[(5-amidino-2- thienyl)methyllamide
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Thrombin, a crucial enzyme in the blood coagulation, has been a target for antithrombotic therapy. Orally active thrombin inhibitors would provide effective and safe prophylaxis for venous and arterial thrombosis. We conducted optimization of a highly efficacious benzamidine-based thrombin inhibitor LB30812 (3, Ki = 3 pM) to improve oral bioavailability. Of a variety of arylamidines investigated at the P1 position, 2,5-thienylamidine effectively replaced the benzamidine without compromising the thrombin inhibitory potency and oral absorption. The sulfamide and sulfonamide derivatization at the N-terminal position in general afforded highly potent thrombin inhibitors but with moderate oral absorption, while the well-absorbable N-carbamate derivatives exhibited limited metabolic stability in S9 fractions. The present work culminated in the discovery of the N-carboxymethyl- and 2,5-thienylamidine-containing compound 22 that exhibits the most favorable profiles of anticoagulant and antithrombotic activities as well as oral bioavilability (Ki = 15 pM; F = 43%, 42%, and 15% in rats, dogs, and monkeys, respectively). This compound on a gravimetric basis was shown to be more effective than a low molecular weight heparin, enoxaparin, in the venous thrombosis models of rat and rabbit. Compound 22 (LB30870) was therefore selected for further preclinical and clinical development.
- Lee, Koo,Park, Cheol Won,Jung, Won-Hyuk,Park, Hee Dong,Lee, Sun Hwa,Chung, Kyung Ha,Park, Su Kyung,Kwon, O. Hwan,Kang, Myunggyun,Park, Doo-Hee,Lee, Sang Koo,Kim, Eunice E.,Yoon, Suk Kyoon,Kim, Aeri
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p. 3612 - 3622
(2007/10/03)
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- Thrombin inhibitors having a lactam at P3
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The present invention provides compounds having a lactam ring at P3 and at P1 have a six-membered heterocyclic ring having two ring nitrogen ring atoms and the remainder of the ring atoms carbon atoms. These compounds have biological activity as active and potent inhibitors of thrombin. Their pharmaceutically acceptable salts, pharmaceutical compositions thereof and methods of using these compounds and pharmaceutical compositions comprising these compounds as therapeutic agents for treatment of disease states in mammals which are characterized by abnormal thrombosis are also described.
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- Non-covalent inhibitors of urokinase and blood vessel formation
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Novel compounds having activity as non-covalent inhibitors of urokinase and having activity in reducing or inhibiting blood vessel formation are provided. These compounds have P1 a group having an amidino or guanidino moiety or derivative thereof. These compounds are useful in vitro for monitoring plasminogen activator levels and in vivo in treatment of conditions which are ameliorated by inhibition of or decreased activity of urokinase and in treating pathologic conditions wherein blood vessel formation is related to a pathologic condition.
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- Novel, potent non-covalent thrombin inhibitors incorporating P3-lactam scaffolds
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Evolution of P1-argininal inhibitor prototypes led to a series of non-covalent P3-7-membered lactam inhibitors 1a-w, featuring novel peptidomimetic units that probe each of the S1, S2, and S3 specificity pockets of thrombin. Rigid P1-arginine surrogates possessing a wide range of basicity (calcd pKa's～neutral-14) were surveyed. The design, synthesis, and biological activity of these targets are presented.
- Ho, Jonathan Z.,Gibson, Tony S.,Semple
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p. 743 - 748
(2007/10/03)
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- Non-covalent inhibitors of urokinase and blood vessel formation
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Novel compounds having activity as non-covalent inhibitors of urokinase and having activity in reducing or inhibiting blood vessel formation are provided. These compounds have Pi a group having an amidino or guanidino moiety or derivative thereof. These compounds are useful in vitro for monitoring plasminogen activator levels and in vivo in treatment of conditions which are ameliorated by inhibition of or decreased activity of urokinase and in treating pathologic conditions wherein blood vessel formation is related to a pathologic condition.
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- Fluorobenzamidrazone thrombin inhibitors: Influence of fluorine on enhancing oral absorption
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LB30057 (1) is a selective and efficacious oral thrombin inhibitor. Fluorine-substitution on the phenylene ring of the benzamidrazone portion in both compound 1 and its derivatives gave, in many cases, enhanced oral absorption in rats while maintaining the intrinsic potency and selectivity. Compound 2 demonstrated a 3-fold increase in absorption.
- Lee, Koo,Jung, Won-Hyuk,Sang, Yeul Hwang,Lee, Sung-Hack
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p. 2483 - 2486
(2007/10/03)
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- Isoxazoline and isoxazole fibrinogen receptor antagonists
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This invention relates to novel isoxazolines and isoxazoles which are useful as antagonists of the platelet glycoprotein IIb/IIIa fibrinogen receptor complex or the vitronectin receptor, to pharmaceutical compositions containing such compounds, processes for preparing such compounds, and to methods of using these compounds, alone or in combination with other therapeutic agents, for the inhibition of platelet aggregation, as thrombolytics, and/or for the treatment of thromboembolic disorders.
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- Discovery of an orally active series of isoxazoline glycoprotein IIb/IIIa antagonists
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Using isoxazoline XR299 (la) as a starting point for the design of highly potent, long-duration GPIIb/IIIa antagonists, the effect of placing lipophilic substituents at positions α and β to the carboxylate moiety was evaluated. Of the compounds studied, it was found that the n-butyl carbamate 24u1,2 exhibited superior potency and duration of ex vivo antiplatelet effects in dogs. Replacement of the benzamidin-4-yl moiety with alternative basic groups, elimination of the isoxazoline stereocenter, and reversal of the orientation of the isoxazoline ring resulted in lowered potency and/or duration of action.
- Xue, Chu-Biao,Wityak, John,Sielecki, Thais M.,Pinto, Donald J.,Batt, Douglas G.,Cain, Gary A.,Sworin, Michael,Rockwell, Arlene L.,Roderick, John J.,Wang, Shuaige,Orwat, Michael J.,Frietze, William E.,Bostrom, Lori L.,Liu, Jie,Higley, C. Anne,Rankin, F. Wayne,Tobin, A. Ewa,Emmett, George,Lalka, George K.,Sze, Jean Y.,Di Meo, Susan V.,Mousa, Shaker A.,Thoolen, Martin J.,Racanelli, Adrienne L.,Hausner, Elizabeth A.,Reilly, Thomas M.,DeGrado, William F.,Wexler, Ruth R.,Olson, Richard E.
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p. 2064 - 2084
(2007/10/03)
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