- PYRAZOLE DERIVATIVES AS CYTOCHROME P450 INHIBITORS
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The present invention provides compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, methods for their preparation, methods for their use, and pharmaceutical formulations comprising them.
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- Second generation tetrahydroquinoline-based protein farnesyltransferase inhibitors as antimalarials
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Substituted tetrahydroquinolines (THQs) have been previously identified as inhibitors of mammalian protein farnesyltransferase (PFT). Previously we showed that blocking PFT in the malaria parasite led to cell death and that THQ-based inhibitors are the most potent among several structural classes of PFT inhibitors (PFTIs). We have prepared 266 THQ-based PFTIs and discovered several compounds that inhibit the malarial enzyme in the sub- to low-nanomolar range and that block the growth of the parasite (P. falciparum) in the low-nanomolar range. This body of structure-activity data can be rationalized in most cases by consideration of the X-ray structure of one of the THQs bound to mammalian PFT together with a homology structural model of the malarial enzyme. The results of this study provide the basis for selection of antimalarial PFTIs for further evaluation in preclinical drug discovery assays.
- Bendale, Pravin,Olepu, Srinivas,Suryadevara, Praveen Kumar,Bulbule, Vivek,Rivas, Kasey,Nallan, Laxman,Smart, Brian,Yokoyama, Kohei,Ankala, Sudha,Pendyala, Prakash Rao,Floyd, David,Lombardo, Louis J.,Williams, David K.,Buckner, Frederick S.,Chakrabarti, Debopam,Verlinde, Christophe L. M. J.,Van Voorhis, Wesley C.,Gelb, Michael H.
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p. 4585 - 4605
(2008/03/13)
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- Organic compounds
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The present invention provides a compound of formula I: Said compound is inhibitor of aldosterone synthase and aromatase, and thus can be employed for the treatment of a disorder or disease mediated by aldosterone synthase or aromatase. Accordingly, the compound of formula I can be used in treatment of hypokalemia, hypertension, congestive heart failure, atrial fibrillation, renal failure, in particular, chronic renal failure, restenosis, atherosclerosis, syndrome X, obesity, nephropathy, post-myocardial infarction, coronary heart diseases, inflammation, increased formation of collagen, fibrosis such as cardiac or myocardiac fibrosis and remodeling following hypertension and endothelial dysfunction, gynecomastia, osteoporosis, prostate cancer, endometriosis, uterine fibroids, dysfunctional uterine bleeding, endometrial hyperplasia, polycystic ovarian disease, infertility, fibrocystic breast disease, breast cancer and fibrocystic mastopathy. Finally, the present invention also provides a pharmaceutical composition.
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Page/Page column 29
(2010/11/26)
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- C17,20-lyase inhibitors I. Structure-based de novo design and SAR study of C17,20-lyase inhibitors.
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Novel nonsteroidal C(17,20)-lyase inhibitors were synthesized using de novo design based on its substrate, 17 alpha-hydroxypregnenolone, and several compounds exhibited potent C(17,20)-lyase inhibition. However, in vivo activities were found to be short-lasting, and in order to improve the duration of action, a series of benzothiophene derivatives were evaluated. As a result, compounds 9h, (S)-9i, and 9k with nanomolar enzyme inhibition (IC(50)=4-9 nM) and 9e (IC(50)=27 nM) were identified to have powerful in vivo efficacy with extended duration of action. The key structural determinants for the in vivo efficacy were demonstrated to be the 5-fluoro group on the benzothiophene ring and the 4-imidazolyl moiety. Superimposition of 9k and 17 alpha-hydroxypregnenolone demonstrated their structural similarity and enabled rationalization of the pharmacological results. In addition, selected compounds were also identified to be potent inhibitors of human enzyme with IC(50) values of 20-30 nM.
- Matsunaga, Nobuyuki,Kaku, Tomohiro,Itoh, Fumio,Tanaka, Toshimasa,Hara, Takahito,Miki, Hiroshi,Iwasaki, Masahiko,Aono, Tetsuya,Yamaoka, Masuo,Kusaka, Masami,Tasaka, Akihiro
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p. 2251 - 2273
(2007/10/03)
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- Imidazolo-5-YL-2anilino-pyrimidines as agents for the inhibition of the cell proliffration
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Compounds of the formula (I): wherein R1, R2, R3, R4, R5, R6, p, q, and n are as defined within and a pharmaceutically acceptable salts and in vivo hydrolysable esters are described. Also described are processes for their preparation and their use as medicaments, particularly medicaments for producing a cell cycle inhibitory (anti-cell-proliferation) effect in a warm-blooded animal, such as man.
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Page/Page column 32
(2010/02/05)
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- A Facile Route to Imidazol-4-yl Anions and Their Reaction with Carbonyl Compounds
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Treatment of N-protected 4-iodoimidazoles 1-3 in CH2Cl2 solution with an etheral solution of ethylmagnesium bromide generates the corresponding imidazol-4-yl anions, which react with carbonyl compounds to give carbinols 4-14 in 60-83percent yield.
- Turner, Richard M.,Lindell, Stephen D.,Ley, Steven V.
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p. 5739 - 5740
(2007/10/02)
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- HISTAMINE DERIVATIVE, PROCESS FOR PREPARING IT AND ITS THERAPEUTIC USE
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The present invention relates to α,β-dimethylhistamine, of the rmula: STR1 in racemic form, or an optical isomer form or mixture of diastereoisomers and its acid addition salts. It may be prepared from an alkyl 2-amino 3-(1H-imidazol-4-yl)-carboxylate.
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- Attempted inhibition of histidine decarboxylase with β aklyl analogues of histidine
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The synthesis of β-methyl-(10b),β-ethyl-(10c), and β-n-hexylhistidine in five steps from 4-(N-triphenyl-methyl) imidazolecarboxaldehyde is described. Neither of the amino acids nor the methyl esters of 10b or 10c were inhibitors of the histidine decarboxylase from rat stomach.
- Kelley,Miller,McLean
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p. 721 - 723
(2007/10/05)
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