The synthesis and SAR studies of a novel N-aryl pyridinone class of p38 kinase inhibitors are described. Systematic structural modifications to the HTS lead, 5, led to the identification of (−)-4a as a clinical candidate for the treatment of inflammatory diseases. Additionally, the chiral synthesis and properties of (−)-4a are described.

Background: As the Malaysian population has reached up to 28.25 million in 2010 and life expectancy of Malaysia has attained up to 71.6 for males and 76.4 for females, a significant increase in elderly morbidity is expected in the coming years. State health department of Sabah, Malaysia, is trying hard to improve the health of its 3.5 million people in Northern Borneo. Kudat and Kota Belud hospitals are covering the medical care needs of about 81,000 and 93,000 populations respectively.Objective: To highlight the hospital burden borne by elderly morbidities in two selected hospitals of Northern Borneo, a review of in-patient records from the above hospitals was done for 2009. All male in-patients aged 60 and above were included.Results: The study revealed the illness pattern of elderly males in two district hospitals. Although hypertension and heart diseases took the highest rank, malaria, tuberculosis and diarrhoea were still found to be a problem for elderly in both hospitals. The male admission for Chronic-obstructive pulmonary disease was significantly higher than female, whereas hospital fatality among male elderly was lower than their female counterparts. Universally, priorities are given to women and children, and hence men's health is often left out of the focus.Conclusions: This study presented a glimpse of male morbidities among elderly population of Sabah, Malaysia. However, results may not reflect the actual morbidity of elderly males in the community as this study was a hospital based retrospective case review. Thus, we recommend a community based survey. (c) 2011 WPMH GmbH. Published by Elsevier Ireland Ltd. All rights reserved.

Starting from an initial HTS screening lead, a novel series of C(5)-substituted diaryl pyrazoles were developed that showed potent inhibition of p38alpha kinase. Key to this outcome was the switch from a pyridyl to pyrimidine at the C(4)-position leading to analogs that were potent in human whole blood based cell assay as well as in a number of animal efficacy models for rheumatoid arthritis. Ultimately, we identified a clinical candidate from this substrate; SD-0006.

Focused SAR studies were carried out around 5-heteroaryl and 1-amide portions of the 2-chlorobenzamide scaffold, resulting in the discovery of a potent, metabolically stable and centrally penetrable antagonist against P2X7 receptor.

SD0006 is a diarylpyrazole that was prepared as an inhibitor of p38 kinase-α (p38α). In vitro, SD0006 was selective for p38α kinase over 50 other kinases screened (including p38γ and p38δ with modest selectivity over p38β). Crystal structures with p38α show binding at the ATP site with additional residue interactions outside the ATP pocket unique to p38α that can confer advantages over other ATP competitive inhibitors. Direct correlation between inhibition of p38α activity and that of lipopolysaccharide-stimulated TNFα release was established in cellular models and in vivo, including a phase 1 clinical trial. Potency (IC50) for inhibiting tumor necrosis factor-α (TNFα) release, in vitro and in vivo, was <200 nmol/l. In vivo, SD0006 was effective in the rat streptococcal-cell-wall-induced arthritis model, with dramatic protective effects on paw joint integrity and bone density as shown by radiographic analysis. In the murine collagen-induced arthritis model, equivalence was demonstrated to anti-TNFα treatment. SD0006 also demonstrated good oral anti-inflammatory efficacy with excellent cross-species correlation between the rat, cynomolgus monkey, and human. SD0006 suppressed expression of multiple proinflammatory proteins at both the transcriptional and translational levels. These properties suggest SD0006 could provide broader therapeutic efficacy than cytokine-targeted monotherapeutics.

The identification and evolution of a series of potent and selective p38 inhibitors is described. p38 inhibitors based on a N-benzyl pyridinone high-throughput screening hit were prepared and their SAR explored. Their design was guided by ligand bound co-crystals of p38α. These efforts resulted in the identification of 12r and 19 as orally active inhibitors of p38 with significant efficacy in both acute and chronic models of inflammation.

In the foregoing studies, it has been proved that the digital reactivity meter can be used for not only sub-criticality measurement but also continuous sub-criticality monitoring during criticality approach. Based on these studies, we investigated the applicability of a digital reactivity meter for continuous sub-criticality monitoring to intervene before a criticality accident occurs that is similar to the Tokai-mura accident in 1999. In our mock up numerical simulation, there are three calculation steps that are (1) reactivity transient calculation, (2) neutron transient calculation and (3) sub-criticality monitoring calculation. The reactivity transient was calculated using two-group diffusion nuclear constants and the neutron transient was calculated using the one-point reactor kinetics. In sub-criticality monitoring, three algorithms for reactivity evaluation were compared. We have investigated which algorithm is the most suitable to use in an actual system. In practice, we also advise use of some filtering algorithm to reduce the neutron transient fluctuation and a warning reactivity to know estimated sub-criticality as earlier as possible.

A mockup experiment of subcriticality measurement with a digital reactivity meter during criticality approach in a PWR was carried out using plant data. There are some difficulties in the direct application of a digital reactivity meter to the subcriticality measurement. Some treatments were needed in using the count rate of Source Range (SR) detector as input signal to the digital reactivity meter. To overcome these difficulties, we proposed a digital reactivity meter combined with a methodology of the modified Neutron Source Multiplication (NSM) method with the fundamental mode extraction. In this study, the neutron source strength was defined as a constant in terms of a known initial stable subcriticality and the neutron signal from a steady state condition. Even though initial stable subcriticality might be contained some errors, the errors of estimated subcriticalities do not depend on the error contribution of initial stable subcriticality when we normalize the estimated subcriticalities with exactly known reference suberiticality. It was proved that the digital reactivity meter could be used not only for the subcriticality measurement or control rod worth measurement but also for the continuous monitoring of the subcriticality during criticality approach.

It has been proposed that a digital reactivity meter can be used for not only subcriticality measurement but also continuous subcriticality monitoring during criticality approach. In this study, a mock up numerical simulation was carried out to investigate some technical issues that still exist. These are sampling interval, time lag of estimated subcriticality due to filtering effect as well as due to the error contribution to the initial reference subcriticality and the way to avoid time lag of estimated subcriticality from safety point of view. It was found that there is influence of sampling interval on the reactivity fluctuation. Filter can cause time lag of estimated subcriticality when a large filter time constant is used. In subcriticality monitoring, the error contribution to the initial reference subcriticality obtained by some design calculation should be investigated to detect accurately an unexpected criticality as earlier as possible. It was known that the negative error contribution to the initial reference subcriticality should be used from safety point of view. We have analytically obtained the relation between the error of the initial reference subcriticality, ramp rate of reactivity addition, warning subcriticality and the margin of the time interval for the counter action.

Applicability of the modified Neutron Source Multiplication (NSM) method with extraction of the fundamental mode to subcriticality measurement has been investigated. This concept can be applied to the control rod worth measurement that is performed during reactor physics tests at periodical inspection of commercial PWRs. Following the feasibility verification in the previous study based on numerical analyses, its applicability has been proven in a more realistic situation; Regarding a withdrawal sequence of control rod banks during the PWR startup as a mockup experiment, subcriticalities with various control rod insertion patterns were estimated based on the modified NSM method. The suberiticality could be evaluated with good accuracy even with the mockup experiment where any special treatments for accurate measurement were not taken into account and furthermore the insensitivity of measuring signals by reactivity changes and their large fluctuations were seen.Some vital treatments for accurate estimation were identified: The reference subcritical state must be as closer to zero as possible. It is necessary to wait long enough for the delayed neutron effect to attenuate after a reactivity change by control rod bank withdrawal. Gamma-ray contamination contained in the detector signals should be corrected.

A modified neutron source multiplication method has been investigated for application to subcriticality measurement in commercial Pressurized Water Reactors (PWRs). This method is based on the extraction of the fundamental mode from measured neutron signals and corrections for spatial effects. In commercial reactors, mainly two types of neutron sources are expected, one from burnt fuels and the other from in-core fixed neutron sources. To calculate the extraction and spatial correction factors, the fixed source problem was solved by the Finite Difference Method (FDM) to explicitly deal with spatial intensities of neutron sources. Sensitivity analysis was carried out to investigate how the accuracy of estimated subcriticality depends on approximation levels of neutron source distributions. It was found that both of the neutron sources should be taken into account. For a pin rod type of the in-core fixed neutron source, a node-wise distribution for which the localized source intensity is averaged over the radial direction in the relevant nodes is applicable, since it can estimate the subcriticality with almost the same accuracy as in the case with a rigid spatial treatment. This ensures that nodal calculations can be used in the evaluation of correction factors instead of burdensome FDM calculations.

본 발명은 하기 화학식 (I)의 화합물 및 제약상 허용되는 그의 염에 관한 것이다. 상기 식 중, R 1 , R 2 , R 3 , R 4 및 R 5 는 본원에 정의된 바와 같다. 이러한 화합물은 비조절된 p38 MAP 키나제 및(또는) TNF 활성에 의해 야기되거나 악화되는 질환 및 증상을 치료하는데 유용하다. 본 발명에는 상기 화합물을 함유하는 제약 조성물, 상기 화합물의 제조 방법 및 상기 화합물을 사용하는 치료 방법이 또한 개시되어 있다. ｐ38 ＭＡＰ 키나제, ＴＮＦ 활성, 치환된 피리디논