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1.
Xiang MA Rybczynski PJ Patel M Chen RH McComsey DF Zhang HC Gunnet JW Look R Wang Y Minor LK Zhong HM Villani FJ Demarest KT Damiano BP Maryanoff BE 《Bioorganic & medicinal chemistry letters》2007,17(23):6623-6628
We have continued to explore spirobenzazepines as vasopressin receptor antagonists to follow up on RWJ-339489 (2), which had advanced into preclinical development. Further structural modifications were pursued to find a suitable backup compound for human clinical studies. Thus, we identified carboxylic acid derivative 3 (RWJ-676070; JNJ-17158063) as a potent, balanced vasopressin V(1a)/V(2) receptor antagonist with favorable properties for clinical development. Compound 3 is currently undergoing human clinical investigation. 相似文献
2.
Numerous transposed sequences of mitochondrial cytochrome oxidase I-II in aphids of the genus Sitobion (Hemiptera: Aphididae) 总被引:4,自引:1,他引:3
Polymerase chain reaction (PCR) products corresponding to 803 bp of the
cytochrome oxidase subunits I and II region of mitochondrial DNA (mtDNA
COI-II) were deduced to consist of multiple haplotypes in three Sitobion
species. We investigated the molecular basis of these observations. PCR
products were cloned, and six clones from one individual per species were
sequenced. In each individual, one sequence was found commonly, but also
two or three divergent sequences were seen. The divergent sequences were
shown to be nonmitochondrial by sequencing from purified mtDNA and Southern
blotting experiments. All seven nonmitochondrial clones sequenced to
completion were unique. Nonmitochondrial sequences have a high proportion
of unique sites, and very few characters are shared between
nonmitochondrial clones to the exclusion of mtDNA. From these data, we
infer that fragments of mtDNA have been transposed separately (probably
into aphid chromosomes), at a frequency only known to be equalled in
humans. The transposition phenomenon appears to occur infrequently or not
at all in closely related genera and other aphids investigated. Patterns of
nucleotide substitution in mtDNA inferred over a parsimony tree are very
different from those in transposed sequences. Compared with mtDNA,
nonmitochondrial sequences have less codon position bias, more even
exchanges between A, G, C and T, and a higher proportion of nonsynonymous
replacements. Although these data are consistent with the transposed
sequences being under less constraint than mtDNA, changes in the
nonmitochondrial sequences are not random: there remains significant
position bias, and probable excesses of synonymous replacements and of
conservative inferred amino acid replacements. We conclude that a
proportion of the inferred change in the nonmitochondrial sequences
occurred before transposition. We believe that Sitobion aphids (and other
species exhibiting mtDNA transposition) may be important for studying the
molecular evolution of mtDNA and pseudogenes. However, our data highlight
the need to establish the true evolutionary relationships between sequences
in comparative investigations.
相似文献
3.
D F McComsey M J Hawkins P Andrade-Gordon M F Addo D Oksenberg B E Maryanoff 《Bioorganic & medicinal chemistry letters》1999,9(10):1423-1428
The thrombin receptor PAR-1 is activated by alpha-thrombin to stimulate cells, including platelets, through the tethered-ligand sequence SFLLRN. We have discovered a novel series of heterocycle-peptide hybrids comprised of a tripeptide segment, such as Cha-Arg-Phe, and an N-terminal heterocyclic group, many of which behave as full PAR-1 agonists. Certain compounds with an aminotriazole group, such as 4 and 16, are nearly as potent as SFLLRN-NH2 in inducing platelet aggregation. Also, some arylethenoyl "N-capped" compounds, such as 52 and 57, exhibit mixed PAR-1 agonist-antagonist activity. 相似文献
4.
Background: Kallistatin, a serine proteinase inhibitor, has vasodilatory and anti-inflammatory properties and is increased in other inflammatory conditions. We measured kallistatin in HIV for the first time, examined its relationship with inflammation, and determined if statin therapy affected levels.
Methods: Kallistatin levels were measured in subjects from a randomized, double-blinded, placebo-controlled trial.
Results: One hundred and thirty-five HIV-infected subjects were included. Kallistatin levels were 28.4?μg/mL at baseline and not affected by rosuvastatin. Levels were correlated with high-sensitivity C-reactive protein (hsCRP), interleukin-6, fibrinogen and insulin resistance.
Conclusions: Kallistatin levels were correlated with some markers of systemic inflammation and should be further explored in the HIV population. 相似文献
5.
BE Maryanoff JC O'Neill DF McComsey SC Yabut DK Luci AC Gibbs MA Connelly 《Bioorganic & medicinal chemistry letters》2012,22(16):5326-5329
Inhibitors of ketohexokinase (KHK) have potential for the treatment of diabetes and obesity. We have continued studies on a pyrimidinopyrimidine series of potent KHK inhibitors by exploring the 2-position substituent (R(3)) that interacts with Asp-27B in the ATP-binding region of KHK (viz. 1, 2; Table 1). We found that increased spacing between the terminal ammonium group and the heterocyclic scaffold (viz. 16-20), such that interaction with Asp-27B is not possible, still results in potent KHK inhibition (IC(50)=15-50nM). We propose a new interaction with Asp-194, which serves to expand the pyrimidinopyrimidine pharmacophore. 相似文献
6.
Zhang HC White KB McComsey DF Addo MF Andrade-Gordon P Derian CK Oksenberg D Maryanoff BE 《Bioorganic & medicinal chemistry letters》2003,13(13):2199-2203
A new generation of indole-based peptide mimetics, bearing a basic amine at the C-terminus, was developed by the agency of two complementary, multistep, trityl resin-based approaches. Thus, we obtained several high-affinity thrombin receptor (PAR-1) ligands, such as 32 and 34. Compounds 32 and 34 were found to bind to PAR-1 with excellent affinity (IC(50)=25 and 35 nM, respectively) and to effectively block platelet aggregation induced by SFLLRN-NH(2) (TRAP-6) and alpha-thrombin. 相似文献
7.
8.
Thrombin receptor (PAR-1) antagonists. Solid-phase synthesis of indole-based peptide mimetics by anchoring to a secondary amide 总被引:1,自引:0,他引:1
Zhang HC McComsey DF White KB Addo MF Andrade-Gordon P Derian CK Oksenberg D Maryanoff BE 《Bioorganic & medicinal chemistry letters》2001,11(16):2105-2109
A novel, 10-step, solid-phase method, based on a secondary amide linker, was developed to construct a diverse library of indole-based SFLLR peptide mimetics as thrombin receptor (protease-activated receptor 1, PAR-1) antagonists. The key steps include stepwise reductive alkylation, urea formation, and Mannich reaction. Screening of the library led to a quick development of the SAR and the significant improvement of PAR-1 activity. 相似文献
9.
Initial verification of the resistance management strategy for Frankliniella
occidentalis (Pergande) (Thysanoptera: Thripidae) in Australia 总被引:2,自引:1,他引:1
Shortly after the initial detection of western flower thrips (WFT), Frankiniella occidentalis (Pergande), in Australia during 1993 a resistance management strategy based on the alternation of chemical groups was implemented. This study aimed to verify this strategy by field testing α-cypermethrin against WFT with and without chemical alternation. Up to 114 times α-cypermethrin resistance (at LC50) was detected and resistance increased with and without chemical alternation; however, chemical alternation did significantly reduce numbers of thrips compared with a nonalternation strategy. Resistance has the potential to undermine the sustainable use of those chemicals to which there is no current detectable resistance. Consequently, chemicals with a high frequency and level of resistance against WFT need to be identified through monitoring and quickly eliminated from WFT chemical control recommendations. 相似文献
10.
We developed a new and simple method to collect sections of a whole brown rice kernel for investigation of histological properties. A single kernel of rice was dehydrated through a graded ethanol series, transferred to xylene, and embedded in paraffin. During sectioning of the blocks using a rotary microtome, we used a special adhesive tape to collect and place the sections on slides so they remained flat. The use of the adhesive tape technique combined with autofluorescence characteristics allowed us to visualize cell walls throughout an entire longitudinal or transverse section of a whole rice kernel. We obtained scanning electron microscopy images of the sections to determine section quality. 相似文献