SAR profiles of spirocyclic nicotinamide derived selective HDAC1/HDAC2 inhibitors (SHI-1:2)

A potent family of spirocyclic nicotinyl aminobenzamide selective HDAC1/HDAC2 inhibitors (SHI-1:2) is profiled. The incorporation of a biaryl zinc-binding motif into a nicotinyl scaffold resulted in enhanced potency and selectivity versus HDAC3, but also imparted hERG activity. It was discovered that increasing polar surface area about the spirocycle attenuates this liability. Compound 12 induced a 4-fold increase in acetylated histone H2B in an HCT-116 xenograft model study with acute exposure, and inhibited tumor growth in a 21-day efficacy study with qd dosing.     

Use of a biological peptide pump to study chronic peptide hormone action in transgenic mice. Direct and indirect effects of angiotensin II on the heart

Angiotensin II is a peptide hormone regulator of blood pressure and fluid balance in mammals. Evidence obtained largely in vitro has also suggested that angiotensin II has growth-promoting effects and that it might thereby contribute to such pathological phenomena as cardiac hypertrophy, a major risk factor for cardiovascular mortality. It has been difficult to test for the direct growth-promoting effects of angiotensin II in vivo, however, because of the generalized effects of the peptide on hemodynamics. To overcome this limitation and to test for cardiac-specific functions of angiotensin II, we generated transgenic mice expressing an angiotensin II-producing fusion protein exclusively in cardiac myocytes. Our findings are the first to distinguish between local and systemic effects of angiotensin II on the heart and introduce a novel technique for studying tissue-specific peptide function.     

The discovery of 6-amino nicotinamides as potent and selective histone deacetylase inhibitors

This communication highlights the development of a nicotinamide series of histone deacetylase inhibitors within the benzamide structural class. Extensive exploration around the nicotinamide core led to the discovery of a class I selective HDAC inhibitor that possesses excellent intrinsic and cell-based potency, acceptable ancillary pharmacology, favorable pharmacokinetics, sustained pharmacodynamics in vitro, and achieves in vivo efficacy in an HCT116 xenograft model.     

Hon-yaku: a biology-driven Bayesian methodology for identifying translation initiation sites in prokaryotes

Background  

Computational prediction methods are currently used to identify genes in prokaryote genomes. However, identification of the correct translation initiation sites remains a difficult task. Accurate translation initiation sites (TISs) are important not only for the annotation of unknown proteins but also for the prediction of operons, promoters, and small non-coding RNA genes, as this typically makes use of the intergenic distance. A further problem is that most existing methods are optimized for Escherichia coli data sets; applying these methods to newly sequenced bacterial genomes may not result in an equivalent level of accuracy.     

Design and synthesis of dipeptidyl nitriles as potent, selective, and reversible inhibitors of cathepsin C

A series of dipeptide nitriles with a thienyl alanine in P2 were identified as potent and selective cathepsin C inhibitors. Incorporation of a substituted cyclopropyl moiety in P1 effectively protects these derivatives against hydrolase activity in whole blood.     

Correspondence among methods of zooplankton biomass measurement in lakes: effect of community composition on optical plankton counter and size-fractionated seston data

The effectiveness of the optical particle counter (OPC) to estimatezooplankton biomass depends on the variability in zooplanktonshape and the presence of interfering particles. In marine environmentswhere zooplankton are composed of similarly shaped copepods,an average shape is relatively easily obtained. However, infreshwater environments, spheroid cladocerans mix with ellipsoidcopepods and make the application of a single morphometric modeldifficult. To expand the use of the OPC to freshwater environments,we developed new ellipsoid models for three common lake types(eutrophic, mesotrophic, and oligotrophic). In addition, weassessed how closely different size fractions of seston correspondedto zooplankton biomass. When expressed in common dry mass units,OPC- and seston-derived zooplankton biomass estimates showeda 1:1 correspondence with taxonomically derived estimates inproductive lakes (r > +0.70, P < 0.001) but not in oligotrophicsystems. OPC ellipse models differed among lake sets (major-to-minoraxis ratio: 1.5 to 2.7) but were not a simple function of thecladoceran-to-copepod ratio. The seston size fraction that providedthe best estimates of zooplankton biomass was smaller in mesotrophiclakes (>200 µm) than in eutrophic or oligotrophic lakes(>500 µm). The presence of algae and rotifers had nodetectable influence on OPC and size-fractionated seston estimates.Overall, these analyses suggest that OPC and seston providereliable estimates of lacustrine zooplankton biomass as longas region-specific ellipse models and size fractions, respectively,are used.     

Non-synonymous polymorphisms in the P2RX 4 are related to bone mineral density and osteoporosis risk in a cohort of Dutch fracture patients

In the present study we investigated whether single nucleotide polymorphisms (SNPs) in the P2RX₄, which alter the P2X₄R function, are associated with the development of osteoporosis and whether an interaction between the P2X₄R and P2X₇R confer a synergistic effect of these two receptors on osteoporosis risk. Patients with fracture (690 females and 231 males, aged ≥50 years) were genotyped for three non-synonymous P2X₄R SNPs. Bone mineral density (BMD) was measured at the total hip, lumbar spine, and femoral neck. Subject carrying the variant allele of the Tyr315Cys polymorphism showed a 2.68-fold (95 % CI, 1.20–6.02) higher risk of osteoporosis compared with wild-type subject. Furthermore, significant lower lumbar spine BMD values were observed in subjects carrying the Cys315 allele as compared with wild-type (0.85 ± 0.17 and 0.93 ± 0.17 g/cm², respectively; p < 0.001). Assuming a recessive model, carriers of the variant allele of the Ser242Gly polymorphism showed increased BMD values at the lumbar spine compare to wild-type subject (1.11 ± 0.35 and 0.92 ± 0.17 g/cm², respectively; p = 0.0045). This is the first study demonstrating an association of non-synonymous polymorphisms in the P2RX₄ and the risk of osteoporosis, suggesting a role of the P2X₄R in the regulation of bone mass.

Electronic supplementary material

The online version of this article (doi:10.1007/s11302-012-9337-0) contains supplementary material, which is available to authorized users.