Discovery and structure-activity relationships of novel selective norepinephrine and dual serotonin/norepinephrine reuptake inhibitors

Novel arylthiomethyl morpholines are potent selective norepinephrine reuptake inhibitors (NERIs) and dual serotonin/norepinephrine reuptake inhibitors (SRI/NERIs). The target compounds were prepared using a stereochemically versatile synthesis featuring an aldol condensation as the key step. One enantiomer of the 2-methoxy-substituted analogue was found to be a potent and selective norepinephrine reuptake inhibitor, whereas the opposite enantiomer was a potent dual serotonin/norepinephrine reuptake inhibitor.     

Design and synthesis of isoquinolines and benzimidazoles as RAF kinase inhibitors

RAF kinase plays a critical role in the RAF-MEK-ERK signaling pathway and inhibitors of RAF could be of use for the treatment of various cancer types. We have designed potent RAF-1 inhibitors bearing novel bicyclic heterocycles as key structural elements for the interaction with the hinge region. In both series exploration of the SAR was focussed on the substitution of the phenyl ring, which binds to the induced fit pocket. Overall, it was confirmed that incorporation of lipophilic substituents was needed for potent Raf inhibition and a number of potent analogues were obtained.     

Inflammatory effects of prostacyclin (PGI2) and 6-oxo-PGF1alpha in the rat paw.

In the rat paw prostacyclin was 5--10 times less potent than PGE2 in causing oedema, and 5 times less potent in potentiating carrageenin-induced oedema, which it did in a dose-related manner. Prostacyclin was 5 times more potent than PGE2 in producing hyperalgesia and as potent as PGE2 in restoring carrageenin-induced hyperalgesia. The effects on oedema were longer lasting than those on hyperalgesia. 6-oxo-PGF1alpha was 500 times less potent than PGE2 in causing oedema by itself and in potentiating carrageenin-induced oedema. It had no hyperalgesic activity in this test.     

N'-[2-(2-thiophene)ethyl]-N'-[2-(5-bromopyridyl)] thiourea as a potent inhibitor of NNI-resistant and multidrug-resistant human immunodeficiency virus-1

The thiophene-ethyl thiourea (TET) compound N′-[2-(2-thiophene)ethyl]-N′-[2-(5-bromopyridyl)]-thiourea (compound HI-443) was five times more potent than trovirdine, 1250 times more potent than nevirapine, 100 times more potent than delavirdine, 75 times more potent than MKC-442, and 50 times more potent than AZT against the multidrug resistant HIV-1 strain RT-MDR with a V106A mutation. HI-443 was almost as potent against the NNI-resistant HIV-1 strain A17 with a Y181C mutation as it was against HTLV_IIIB. The activity of HI-443 against A17 was ten times more potent than that of trovirdine, 2083 times more potent than that of nevirapine, and 1042 times more potent than that of delavirdine. HI-443 inhibited the replication of the NNI-resistant HIV-1 strain A17 variant with Y181C plus K103N mutations in RT with an IC₅₀ value of 3.3 μM, whereas the IC₅₀ values of trovirdine, nevirapine, and delavirdine were all >100 μM. These findings establish the novel thiophene containing thiourea compound HI-443 as a novel NNI with potent antiviral activity against NNI-sensitive, NNI-resistant and multidrug-resistant strains of HIV-1.     

Highly potent propargylamine and allylamine inhibitors of bovine plasma amine oxidase

Propargylamine was reported many years ago to be a mechanism-based inhibitor of bovine plasma amine oxidase (BPAO), though the potency was modest and allylamine was a substrate. Herein, selected 3-substituted propargylamines and allylamines were found to be potent time-dependent inactivators of BPAO, exhibiting IC(50) values of 2-13 microM at 30 degrees C, making them the most potent BPAO inhibitors reported to date. The most potent compound, trans-3-chloroallylamine, was previously found not to inhibit the flavin-dependent monoamine oxidase (the cis isomer did), and thus appears to be a highly selective inhibitor.     

Design, synthesis and evaluation of trifluoromethane sulfonamide derivatives as new potent and selective peroxisome proliferator-activated receptor alpha agonists

Starting from the structure of 5, a two-step strategy was applied to identify a new generation of trifluoromethane sulfonamides as potent PPARalpha agonists. Synthesis, in vitro and in vivo evaluation of the most potent compound are reported.     

Synthesis and biological evaluation of 4-amino derivatives of benzimidazoquinoxaline, benzimidazoquinoline, and benzopyrazoloquinazoline as potent IKK inhibitors

We have recently identified BMS-345541 (1) as a highly selective and potent inhibitor of IKK-2 (IC50 = 0.30 microM), which however was considerably less potent against IKK-1 (IC50 = 4.0 microM). In order to further explore the SAR around the imidazoquinoxaline tricyclic structure of 1, we prepared a series of tetracyclic analogues (7, 13, and 18). The synthesis and biological activities of these potent IKK inhibitors are described.     

Synthesis and evaluation of antiplatelet activity of trihydroxychalcone derivatives

In an effort to develop potent antiplatelet agents, a series of trihydroxychalcones was synthesized and screened in vitro for their inhibitory effects on washed rabbit platelet aggregation induced by arachidonic acid (100 microM) and collagen (10 microg/ml). Of five compounds with potent inhibitory effects on arachidonic acid- and collagen-induced platelet aggregation, compound 4e was found to be the most potent. The structure-activity relationships suggested that antiplatelet activity was governed to a greater extent by the substituent on B ring of the chalcone template, and most of the active compounds had methoxy or dimethoxy groups on B ring.     

Synthesis and evaluation of a spiro-isobenzofuranone class of histamine H3 receptor inverse agonists

Spiro-isobenzofuranones 1a and 1b were discovered as potent, selective, and brain-penetrable non-imidazole H3 receptor inverse agonists. Our corporate sample collection was screened to identify 2a as a lead. Recognizing the right-hand portion of 2a as an essential pharmacophore, an extensive screen of the left-hand piperidine portion was carried out to yield the potent spiro-derivatives 2t-x. Spiro-isobenzofuranone 2x, the most potent among the derivatives, was converted to the corresponding amide 1a, which possessed dramatically improved H3 activity (IC(50)=0.72 nM; more than 20-fold improvement over 2x). Further elaboration led to the identification of 1b, a 5-methoxy derivative with an IC(50) of 0.54 nM. Our studies demonstrated that derivatives 1a and 1b to be potent, selective, and brain-penetrable H3 inverse agonists.     

The genetic activity of N6-hydroxyadenine and 2-amino-N6-hydroxyadenine in Escherichia coli, Salmonella typhimurium and Saccharomyces cerevisiae

The genetic activity of 2-amino-N6-hydroxyadenine or 2-amino-N-hydroxylaminopurine (AHA) and N6-hydroxyadenine or 6-N-hydroxylaminopurine (HAP) was studied in S. typhimurium, E. coli and Saccharomyces cerevisiae strains. AHA was a more potent mutagen for bacteria and a less potent mutagen for yeast than HAP. The mutagenic activity of analogs was not influenced by excision, mutagenic or double-strand DNA repair mutations. On the other hand, the uvrBdel mutation has a drastic effect on the mutagenicity and toxicity of both analogs in the Salmonella strains studied. HAP was a very potent mutagen in yeast with a low capability of inducing mitotic recombination contrary to common mutagens, possessed unique intergenic specificity and was able to induce mutations in diploids at rather high frequency.     

Nucleoside imidodiphosphates synthesis and biological activities.

The synthesis of imidodiphosphate analogues of natural nucleoside 5'-diphosphates including adenosine 5'-imidodiphosphate (4a), guanosine 5'-imidodiphosphate (4b), 2'-deoxyadenosine 5'-imidodiphosphate (4c), and 2'-deoxy-guanosine 5'-imidodiphosphate (4d) has been accomplished for the first time. These compounds are the products of the reaction between nucleosides and trichloro [(dichlorophosphoryl)imido] phosphorane in trimethyl phosphate. Some of the major by-products of the reaction including 5'-deoxy-5'-chloro nucleosides are discussed. Compounds 4b, 4c, and 4d are potent inhibitors of ecto-5'-nucleotidase whereas compound 4a also active but less potent inhibitor. Compound 4b is the most potent inhibitor of phosphoribosyl pyrophosphate (PPRP) synthetase which follows by 4c, 4d and 4a. All of these compounds were more potent inhibitor of PPRP-synthetase than ADP or GDP. Ribavirin imidodiphosphate (4e) was also synthesized and tested for its inhibitory effect on ecto-5'-nucleotidase, PPRP-synthetase as well as IMP dehydrogenase. Compound 4e is the most potent inhibitor of IMP dehyrogenase but was a weak inhibitor of the other two enzymes. compound 4a, 4b, 4c and 4d are weak inhibitors of IMP dehydrogenase.     

Acute and chronic antiinflammatory profile of the ivy plant, Hedera helix, in rats.

Hedera helix is a plant well-known as ivy or English ivy, and a member of the Araliaceae family. In the present study, we tested the possible antiinflammatory effects of a crude saponin extract (CSE) and a saponin's purified extracts (SPE) of Hedera helix in carrageenan- and cotton-pellet-induced acute and chronic inflammation models in rats. Both the CSE and SPE of Hedera helix were found to have antiinflammatory effects. The most potent drug screened was indomethacin (89.2% acute antiinflammatory effect), while the most potent extract screened was the CSE of Hedera helix at 100 and 200 mg/kg body wt. doses with 77% acute antiinflammatory effects. For testing chronic antiinflammatory (antiproliferative) effects, the cotton-pellet-granuloma test was conducted. Indomethacin was found to be the most potent drug in the chronic phase of inflammation, with 66% effect. The SPE of Hedera helix was more potent than the CSE in its chronic antiinflammatory effect (60% and 49%, respectively).     

Synthesis and antibacterial activity of oxazolidinone containing sulphonyl group

A series of oxazolidinone derivatives carrying sulphonyl group was synthesized and their antibacterial activity was evaluated in vitro. Many of such compounds demonstrated potent antibacterial activity. The activity of a novel compound (YC-20) was 2-4-fold more potent than that of linezolid.     

Thyroid Hormones and Derivatives Inhibit Flunitrazepam Binding

Thyroid hormones and their derivatives were found to inhibit [3H]flunitrazepam binding stereospecifically and in a monophasic manner. Among the compounds tested, D-thyroxine was the most potent inhibitor (IC50 = 0.5 microM). The naturally occurring L-thyroxine was about 40-fold less potent (IC50 = 20 microM). The structure-activity relationships seem to imply that the thyronine base has the principal role in the inhibition of benzodiazepine receptor binding. The type of inhibition was examined with the most potent inhibitor, D-thyroxine, by Scatchard analysis. The apparent dissociation constant (KD) of the [3H]flunitrazepam binding increased and the receptor density (Bmax) decreased as a function of D-thyroxine concentration; this is characteristic of mixed-type inhibition.     

Design,synthesis and biological evaluation of novel indole derivatives as potential HDAC/BRD4 dual inhibitors and anti-leukemia agents

HDAC inhibitors and BRD4 inhibitors were considered to be potent anti-cancer agents. Recent studies have demonstrated that HDAC and BRD4 participate in the regulation of some signal paths like PI3K-AKT. In this work, a series of indole derivatives that combine the inhibitory activities of BRD4 and HDAC into one molecule were designed and synthesized through the structure-based design method. Most compounds showed potent HDAC inhibitory activity and moderate BRD4 inhibitory activity. In vitro anti-proliferation activities of the synthesized compounds were also evaluated. Among them, 19f was the most potent inhibitor against HDAC3 with IC₅₀ value of 5 nM and BRD4 inhibition rate of 88% at 10 μM. It was confirmed that 19f could up-regulate the expression of Ac-H3 and reduce the expression of c-Myc by western blot analysis. These results indicated that 19f was a potent dual HDAC/BRD4 inhibitor and deserved further investigation.     

Synthesis and biological evaluation of sulfonylhydrazone-substituted imidazo[1,2-a]pyridines as novel PI3 kinase p110alpha inhibitors

We have previously reported the imidazo[1,2-a]pyridine derivative 4 as a novel p110alpha inhibitor; however, although 4 is a potent inhibitor of p110alpha enzymatic activity and tumor cell proliferation in vitro, it is unstable in solution and ineffective in vivo. To increase stability the pyrazole of 4 was replaced with a hydrazone and a moderately potent p110alpha inhibitor 7a was obtained. Subsequent optimization of 7a afforded exceptionally potent p110alpha inhibitors, including 8c and 8h, with IC(50) values of 0.30 nM and 0.26 nM, respectively; to the best of our knowledge, these compounds are the most potent PI3K p110alpha inhibitors reported to date. Compound 8c was also stable in solution and exhibited significant anti-tumor effectiveness in vivo.     

Design and campaign synthesis of piperidine- and thiazole-based histone deacetylase inhibitors

A lead benzamide, 3, was identified as a potent and low molecular weight histone deacetylase (HDAC) inhibitor. Optimization led to 16d, demonstrating an excellent balance of efficacy and non-efficacy properties, along with very desirable in vivo DMPK. The final compounds presented are >1000-fold more potent than the initial screen hit, an improvement in potency which was achieved with a concomitant significant improvement in all the main non-efficacy properties.     

The discovery and synthesis of novel adenosine receptor (A(2A)) antagonists

In high throughput screening of our file compounds, a novel structure 1 was identified as a potent A(2A) receptor antagonist with no selectivity over the A1 adenosine receptor. The structure-activity relationship investigation using 1 as a template lead to identification of a novel class of compounds as potent and selective antagonists of A(2A) adenosine receptor. Compound 26 was identified to be the most potent A(2A) receptor antagonist (Ki = 0.8 nM) with 100-fold selectivity over the A1 adenosine receptor.     

Regional Heterogeneity of L-Glutamate and L-Aspartate High-Affinity Uptake Systems in the Rat CNS

The high-affinity uptake of L-[3H]glutamate and L-[3H]aspartate into synaptosomes prepared from rat cerebral cortical, hippocampal, and cerebellar tissue was reduced by a number of structural analogues of L-glutamate and L-aspartate. threo-3-Hydroxy-L-aspartic acid was a more potent inhibitor of L-glutamate uptake than of L-aspartate uptake in the cerebral cortex, but not in the hippocampus or cerebellum. A similar pattern of selectivity was observed for cis-1-aminocyclobutane-1,3-dicarboxylic acid. Dihydrokainate was also more potent against L-glutamate than against L-aspartate in the cerebral cortex, but in the hippocampus, it was more potent against L-aspartate than against L-glutamate. By contrast, L-alpha-aminoadipate was significantly more potent in the cerebellum than in the cerebral cortex and hippocampus as an antagonist of both L-glutamate and L-aspartate. These results support other evidence that there is regional heterogeneity in acidic amino acid uptake sites and that the amino acids L-glutamate and L-aspartate may be taken up by a number of transport systems with overlapping substrate specificity but different inhibitor profiles.