New progesterone esters as 5alpha-reductase inhibitors

The pharmacological activity of four new progesterone derivatives: 4-bromo-17alpha-(p-fluorobenzoyloxy)-4-pregnene-3,20-dione (7), 4-bromo-17alpha-(p-bromobenzoyloxy)-4-pregnene-3,20-dione (8), 4-bromo-17alpha-(p-chlorobenzoyloxy)-pregnene-3,20-dione (9) and 4-bromo-17alpha-(p-toluoyloxy)-4-pregnene-3,20-dione (10) was determined. These compounds were evaluated as 5alpha-reductase inhibitors on gonadectomized hamster seminal vesicles and flank organs. The pharmacological data of this study indicate that compounds 7 and 9 having at C-17 p-fluorobenzoyloxy and p-chlorobenzoyloxy ester functions respectively showed the highest antiandrogenic effect as measured by the reduction of the weight of the seminal vesicles. In the flank organ model, the same compounds 7 and 9 exhibited a smaller diameter, 1.8 and 1.0 mm, respectively, than the commercially available finasteride 3 (2.3 mm), thus indicating a higher inhibitory effect on 5alpha-reductase enzyme. Steroid 7 showed a higher inhibitory activity on the conversion of T to DHT (Fig. 3) than the presently used finasteride, thus indicating a higher antiandrogenic effect. The nonsubstituted benzoyloxy ester (compound 15) showed a lower antiandrogenic activity as measured in the seminal vesicles model than the p-substituted benzoyloxy compounds.     

Synthesis of novel 3,4-diaryl-5-aminopyrazoles as potential kinase inhibitors

Synthesis of a diverse series of novel 3,4-diaryl-5-aminopyrazoles as candidates in the development of new protein kinase inhibitors is reported for the first time. In the course of a wider study into bisindolylmaleimide (BIM) derivatives, we examined a novel 5-aminopyrazole heterocyclic moiety as a structural analogue of the highly potent VEGF-R2/3 inhibitor pyrrole-2-one (8). The versatile nature of this pharmacophore allows considerable scope for derivatisation and hence exploration of structure activity relationships. Consequently, a variety of structural modifications were used in order to diversify the aminopyrazole ring substituents. Bicyclic derivatives of the parent aminopyrazoles (11, 12) were also synthesised as a means of probing the kinase active site, leading to formation of complex planar pyrimidine moieties. This work provides the framework for new explorations into kinase inhibition and critical investigations into selectivity of inhibitory activity.     

Facile and regioselective synthesis of novel 2,4-disubstituted-5-fluoropyrimidines as potential kinase inhibitors

2,4-Disubstituted-5-fluoropyrimidine is a biologically active molecular core seen in various anticancer agents such as 5-fluorouracil (5-FU). As part of a programme aimed at discovering kinase inhibitors, routes to two series of novel compounds (5-fluoropyrimidine-2-carboxamides and 5-fluoropyrimidine-4-carboxamides) were successfully executed. For the first series, regioselective substitution at the 4-position of the pyrimidine with an amine (HNR¹R²) was achieved, followed by preparation of the amide at the 2-position. The route to the second series involved introduction of the methoxy protecting group at the 4-position, which allowed subsequent amine substitution to occur at the 2-position. The 4-amide substituent was finally introduced by direct conversion of the 4-methoxy into a 4-chloro group followed by transformation into an amide by palladium catalysis.     

New platelet aggregation inhibitors

From a cultured broth of Streptomyces matensis A-6621, we isolated three new platelet aggregation inhibitors designated as PI-080, PI-085 and PI-087. The structures of these compounds were established by spectral and chemical methods.     

Synthesis and biological evaluation of 5-arylfuro[2,3-d]pyrimidines as novel dihydrofolate reductase inhibitors

A series of about fifty novel 5-arylfuro[2,3-d]pyrimidine derivatives were synthesized as potential inhibitors of dihydrofolate reductase (DHFR) arising from different species. Weak enzyme inhibition was observed for most of the compounds, with only a few reaching IC50 values less than 30 microM. With regards to antibacterial and anti-malarial potency, only seven compounds showed a modest in vitro activity against some bacteria strains and only three products proved significantly active against P. falciparum.     

A novel class of inhibitors for human steroid 5 alpha-reductase: phenoxybenzoic acid derivatives. I.

In a search for novel nonsteroidal inhibitors of human prostatic 5 alpha-reductase, we found a new series of phenoxybenzoic acid derivatives to be potent human prostatic 5 alpha-reductase inhibitors. Among them, 4-(biphenyl-4-yloxy)benzoic acid derivatives (2n, YM-31758), 2o and 2s showed more potent inhibitory activities than finasteride with IC50 values of 0.87, 0.67 and 0.56 nM, respectively. The optimized structures for the phenoxybenzoic acid derivatives 2d-2i were calculated by molecular modeling analysis, and the favorable distance between the carbon of the carboxyl group and the centroid of the phenyl group (benzene ring C) was found to be in the 9-11 A range.     

4-(Benzoylindolizinyl)butyric acids; novel nonsteroidal inhibitors of steroid 5alpha-reductase. III.

A novel series of indolizinebutyric acids with various benzoyl substituents was synthesized to develop nonsteroidal inhibitors of steroid 5alpha-reductase, and the structure-activity relationships in this series were studied. We previously reported the structure-activity relationships in a series of indolebutyric acids as well as the discovery of the novel nonsteroidal 5alpha-reductase inhibitor, FK143. We have now made other modifications to this compound to improve in vivo inhibitory activity. By altering the heterocyclic nucleus and changing the benzoyl substituent we have succeeded in identifying the strongly active compound, FK687, (S)-4-[1-[4-[[1-(4-isobutylphenyl)butyl]oxy]benzoyl]indolizin-3-yl]butyric acid, which displays strong in vitro inhibitory activity against the human enzyme and in vivo inhibitory activity against the castrated young rat model. This compound should be a useful agent for the treatment of benign prostatic hyperplasia.     

New quinoxalines with nitrogen functions in the side chain. Potential inhibitors of 5-HT3

Starting with benzofuroxane 1 , 2-ethoxy-carbonyl-3-methylquinoxaline 1,4-dioxide 7 is obtained. From this compound different amides 5a-q and amino esters 6a-c are obtained. From 2-amino-3-cyanoquinoxaline 1,4-dioxide 7 , new amidines 9 , [5,4-b]pyrimido 10 and [6,5-b]diazepinoquinoxalines 11 were prepared.     

Discovery of 2,4-dimethoxypyridines as novel autophagy inhibitors

Autophagy is a catabolic process, which mediates degradation of cellular components and has important roles in health and disease. Therefore, small molecule modulators of autophagy are in great demand. Herein, we describe a phenotypic high-content screen for autophagy inhibitors, which led to the discovery of a dimethoxypyridine-based class of autophagy inhibitors, which derive from previously reported, natural product-inspired MAP4K4 inhibitors. Comprehensive structure-activity relationship studies led to a potent compound, and biological validation experiments indicated that the mode of action was upstream or independent of mTOR.     

Steroidal nitrone inhibitors of 5α-reductase

This paper describes the rational design and synthesis of novel inhibitors of human steroid 5α-reductase. Steroidal nitrones were synthesised via an eight-step sequence from epiandrosterone and were tested for activity against type I and II 5α-reductase isozymes. Judicious placement of the nitrone into the steroid A-ring provided an effective and stable transition-state mimic of the postulated enolate intermediate involved in the conversion of testosterone into dihydrotestosterone.     

Synthesis of novel 4-(2-amino-5-thiazolyl)-pyrimidine-2-amines as potential protein kinase inhibitors

Abstract  A short and efficient sequence for the synthesis of a series of 4-(2-amino-5-thiazolyl)-pyrimidine-2-amines was developed. 1-Phenyl-2-(6-pyrimidinyl)-ethanones, obtained via Weinreb’s methodology, were used in a Hantzsch thiazole cyclization reaction, followed by introduction of the aniline moieties via nucleophilic substitution. Graphical abstract        

New polyphenolic 5'-nucleotidase inhibitors isolated from the wine grape "Koshu" and their biological effects

New 5'-nucleotidase inhibitors designated as NPF-88BU-IA, NPF-88BU-IB, NPF-88BU-IIA and NPF-88BU-IIB, respectively, were isolated from the seeds and skin of the wine grape "Koshu". They were purified by solvent extraction, dialysis, and reversed-phase high performance liquid chromatography (HPLC). Their physico-chemical properties revealed these compounds to be polyphenolic substances. The average relative molecular masses of the four were estimated by gel permeation chromatography (GPC) analysis to be 7850, 5950, 11900, and 11300, respectively. They strongly inhibited 5'-nucleotidase activities from snake venom and rat liver membrane, and displayed significant therapeutic activity against Ehrlich ascites carcinoma. They also showed inhibitory effects on the growth of Streptococcus mutans MT8148(c), a primary cariogenic bacterium. Furthermore, these 5'-nucleotidase inhibitors inhibited the glucan formation from sucrose. These results suggest that the 5'-nucleotidase inhibitors can prevent the cause of caries of tooth.     

Synthesis of 5-substituted-1H-indol-2-yl-1H-quinolin-2-ones: a novel class of KDR kinase inhibitors

[reaction: see text] A number of approaches for the synthesis of the 1H-indol-2-yl-1H-quinolin-2-one ring system found in the potent and selective KDR kinase inhibitor 1 are described. The preparation and reaction of trimethylsilylnitrobenzene 26 with 2-methoxy-3-quinolinecarboxaldehyde 28 afforded alcohol 30, which was the key intermediate for the preparation of the target compounds. Conversion of alcohol 30 to either nitroketone 36 or nitrostyrene 45 set the stage for reductive cyclization and the formation of indole 25. The quinolin-2-one functionality was unmasked in the last step to provide compound 1 in 56-60% overall yield from readily available starting materials.     

A novel class of inhibitors for human steroid 5alpha-reductase: synthesis and biological evaluation of indole derivatives. II

In a search for novel nonsteroidal inhibitors of human prostatic 5alpha-reductase, we found a new series of indole derivatives that showed potent inhibitory activities for the human enzyme. Among them, 4-[(1-benzyl-1H-indol-5-yl)oxyl-3-chlorobenzoic acid (2d, YM-32906) showed more potent inhibitory activity than finasteride with an IC50 value of 0.44 nM. 3-Chloro-4-[[1-(4-phenoxybenzyl)-1H-indol-5-yl]oxy]benzoic acid (2m) showed inhibitory activities for both human and rat prostatic 5alpha-reductase with IC50 values of 2.1 and 73 nM, respectively. The synthesis and structure-activity relationships of these indole derivatives are presented.     

Design and novel synthesis of aryl-heteroaryl-imidazole MAP kinase inhibitors

Inhibitors of the MAP kinase p38, potentially useful for the treatment of rheumatoid arthritis and inflammatory diseases, were found to exhibit antifungal activity. We have developed a new diversity-oriented strategy leading to concise and efficient syntheses of known and new members of this compound class. The strategy is based on carboncarbon cross-coupling reactions using N-protected 4,5-diiodo-imidazoles as the starting templates.     

Structures of the muraymycins,novel peptidoglycan biosynthesis inhibitors

The muraymycins, a family of nucleoside-lipopeptide antibiotics, were purified from the extract of Streptomyces sp. LL-AA896. The antibiotics were purified by chromatographic methods and characterized by NMR spectroscopy, degradation studies, and mass spectrometry. The structures of 19 compounds were established. The muraymycins constitute a new antibiotic family whose core structure contains a glycosylated uronic acid derivative joined by an aminopropane group to a hexahydro-2-imino-4-pyrimidylglycyl residue (epicapreomycidine) containing dipeptide that is further extended by a urea-valine moiety. Members of this family show broad-spectrum in vitro antimicrobial activity against a variety of clinical isolates (MIC 2 to >64 mug/mL). The muraymycins inhibited peptidoglycan biosynthesis. The fatty acid substituent and the presence or absence of the amino sugar play important roles in biological activity. One of the most active compounds, muraymycin A1, demonstrated protection in vivo against Staphylococcus aureus infection in mice (ED50 1.1 mg/kg).