Discovery of potent selective bioavailable phosphodiesterase 2 (PDE2) inhibitors active in an osteoarthritis pain model. Part II: optimization studies and demonstration of in vivo efficacy.

Selective phosphodiesterase 2 (PDE2) inhibitors are shown to have efficacy in a rat model of osteoarthritis (OA) pain. We identified potent, selective PDE2 inhibitors by optimizing residual PDE2 activity in a series of phosphodiesterase 4 (PDE4) inhibitors, while minimizing PDE4 inhibitory activity. These newly designed PDE2 inhibitors bind to the PDE2 enzyme in a cGMP-like binding mode orthogonal to the cAMP-like binding mode found in PDE4. Extensive structure activity relationship studies ultimately led to identification of pyrazolodiazepinone, 22, which was >1000-fold selective for PDE2 over recombinant, full length PDEs 1B, 3A, 3B, 4A, 4B, 4C, 7A, 7B, 8A, 8B, 9, 10 and 11. Compound 22 also retained excellent PDE2 selectivity (241-fold to 419-fold) over the remaining recombinant, full length PDEs, 1A, 4D, 5, and 6. Compound 22 exhibited good pharmacokinetic properties and excellent oral bioavailability (F=78%, rat). In an in vivo rat model of OA pain, compound 22 had significant analgesic activity 1 and 3h after a single, 10 mg/kg, subcutaneous dose.

Discovery of potent, selective, bioavailable phosphodiesterase 2 (PDE2) inhibitors active in an osteoarthritis pain model, part I: transformation of selective pyrazolodiazepinone phosphodiesterase 4 (PDE4) inhibitors into selective PDE2 inhibitors.

We identified potent, selective PDE2 inhibitors by optimizing residual PDE2 activity in a series of PDE4 inhibitors, while simultaneously minimizing PDE4 activity. These newly designed PDE2 inhibitors bind to the PDE2 enzyme in a cGMP-like mode in contrast to the cAMP-like binding mode found in PDE4. Structure activity relationship studies coupled with an inhibitor bound crystal structure in the active site of the catalytic domain of PDE2 identified structural features required to minimize PDE4 inhibition while simultaneously maximizing PDE2 inhibition.

First report on rhinoceros from the late Neogene Qin Basin of Shanxi, China.

Dihoplus is a rhinoceros distributed across East Asia and Europe from the Late Miocene to Pliocene. This study describes a new skull from the Qin Basin in Shanxi Province, China, referred to as Dihoplus ringstroemi, which has long been debated in taxonomic identity. This skull confirms that D. ringstroemi is an independent species and reveals the presence of the upper incisor and variations in the degree of constriction of the two lingual cusps of upper cheek teeth. In addition, the new skull indicates that the Qin Basin has a late Neogene sediment and fauna comparable to that of the Yushe Basin.

Reproduction of a fossil rhinoceros from 18 mya and origin of litter size in perissodactyls.

Reproductive strategy is among the most important characteristics of organism. Here, we report reproductive strategy of singleton pregnancy of a fossil rhinoceros, Plesiaceratherium gracile, from 18 mya of the Shanwang Basin, China. Dental and body development data revealed that after birth, the calf of P. gracile is breastfed for 2-3 years; at approximately 5 years of age, when the M2 tooth is slightly worn, the female has already reached sexual maturity and attained a size close to that of an adult and could give birth to the first calf. Furthermore, given litter size is phylogenetically conservative and closely correlates with body size, we conclude that the litter size of perissodactyls is determined by the singleton pregnancy since the Eocene. By contrast, other reproductive traits are highly variable and have a different pace of evolution, and traits observed in living rhinoceroses have been evolving at least since 18 mya.

[Soil Respiration in Response to Different Ridge/Furrow Ratios and Its Relationship with Soil Moisture and Temperature Under Ridge-Furrow Planting Patterns].

This study aimed to explore soil respiration in response to soil moisture and soil temperature subjected to different ridge/furrow ratios under various planting patterns. Traditional flat planting and three different ridge-furrow plantings with altering ridge/furrow ratios, i. e. 20:40 cm (P40); 30:30 cm (P30); 40:20 cm (P20), were performed in the present study. Soil respirations among different planting patterns were compared. Their relationships with soil moisture and soil temperature were also analyzed. The results showed that soil respiration flux of four planting patterns reached its minimum value during the wintering stage, started to rise during the returning green stage until it reached a peak value at the flowering stage, and decreased gradually when reaching the maturity stage. The magnitude of soil respiration flux in three ridge-furrow planting patterns followed this order: P40 > P30 > P20, which implied that increasing ridge width could improve soil respiration by 1.2%-18.4%. In addition, soil respiration fluxes of three ridge-furrow plantings patterns were significantly higher than those under conditional patterns during the seedling stage (P<0.05). The soil temperature of ridge-furrow planting patterns was higher than that of the conditional flat pattern from the seeding stage to the wintering stage, but was converse from the jointing stage to the maturity stage. Moreover, three ridge-furrow planting patterns have shown significant effect on preserving soil water storage in comparison with the conditional flat pattern. In general, increasing the width of the ridge increased soil water storage due to less rainfall from the seedling stage to the jointing stage. The correlation analysis indicated a positive and significant correlation coefficient between soil respiration and soil temperature (P<0.01). Correlation coefficients in case of P40 and P30 were higher than those in P20 and the conditional flat pattern. The quadratic model of two-factor soil moisture and soil temperature could explain 61.7%-74.1% of variations in soil respiration. The single factor of the soil temperature model could explain 50.3%-68.2% of variations in soil respiration. Those results could provide a theory basis for further evaluation of ecological effect on the ridge-furrow planting patterns.