We report the discovery of 7-oxo-2,4,5,7-tetrahydro-6 H-pyrazolo[3,4- c]pyridine derivatives as a novel class of receptor interacting protein 1 (RIP1) kinase inhibitors. On the basis of the overlay study between HTS hit 10 and GSK2982772 (6) in RIP1 kinase, we designed and synthesized a novel class of RIP1 kinase inhibitor 11 possessing moderate RIP1 kinase inhibitory activity and P-gp mediated efflux. The optimization of the core structure and the exploration of appropriate substituents utilizing SBDD approach led to the discovery of 22, a highly potent, orally available, and brain-penetrating RIP1 kinase inhibitor with excellent PK profiles. Compound 22 significantly suppressed necroptotic cell death both in mouse and human cells. Oral administration of 22 (10 mg/kg, bid) attenuated disease progression in the mouse experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). Moreover, analysis of structure-kinetic relationship (SKR) for our novel chemical series was also discussed.

A series of heterobimetallic porphyrin pincer palladium complexes have been synthesized through direct cyclometalation of β,β‘-dipyridylporphyrin. X-ray analyses elucidated their highly distorted structures of porphyrin cores induced by the outer metalation. The catalytic activity has been investigated in the typical Heck reaction of iodobenzene with butyl acrylate. These complexes exhibit markedly different catalytic activities in the initial phase of the reaction, depending on the central metals.

Asymmetric 1,3-rearrangement of an alkynyl group of alkynyl alkenyl carbinols giving β-alkynylketones took place in high yields with high enantioselectivity in the presence of a hydroxyrhodium/(R)-binap catalyst. The present method including a key β-alkynyl elimination step in the catalytic cycle is synthetically equivalent to the asymmetric conjugate addition of terminal alkynes to β-substituted enones.

Highly regioselective and efficient borylation of a variety of porphyrins has been achieved by reaction with bis(pinacolato)diboron through C-H bond activation under iridium catalysis on the basis of the synthetic protocol developed by Miyaura, Hartwig, and Smith. A boryl group can be selectively introduced at sterically uncongested positions in the peripheral aryl groups of porphyrin substrates whose peripheral beta-positions are sterically hindered. Curiously, beta substituents adjacent to the aryl group to be borylated have unexpectedly large effects on the regioselectivity, because the iridium catalyst can discriminate between subtle steric differences. Chemoselective borylation was also achieved for several functionalized porphyrins. This borylation protocol can be applied to various monomeric and oligomeric functional porphyrins, hence offering an efficient route to elaborate multiporphyrin-based molecular constructs.

Rhodium-catalyzed asymmetric conjugate alkynylation of α,β-unsaturated ketones giving β-alkynylketones took place in high yields with high enantioselectivity. The reaction was realized by use of (triisopropylsilyl)acetylene combined with (R)-DTBM-segphos as a chiral phosphine ligand, where the sterically bulky substituents on the silicon and phosphorus atoms suppress the alkyne dimerization.

We conducted an atmospheric pollen survey using a Durham sampler from 1983 through 1998 in Toyama City, Japan. We investigated yearly changes in the pollen season of Japanese cedar Cryptomeria japonica and analyzed the relationships between climatic factors and changes in the pollen counts. The results were as follows: (1) The first day of the Japanese cedar pollen season advanced from mid-March to late February. The yearly change in the first day was significantly associated with the mean temperature in February. (2) An increase in total pollen count was significantly associated with the mean temperature in the previous July. (3) The duration of the pollen season was suggested to be associated with the total pollen count. These results indicate that climate change, especially increasing global warming, influences the early pollen scatter and increase in pollen count as well as elongation of pollen season of Japanese cedar. Further study will be needed to clarify its effect on the health of pollen-allergy patients.

A directly Pt(IV)-bridged cofacial diporphyrin has been synthesized by the cyclometalation reaction of beta-pyridylporphyrin with a Pt(IV) salt. Upon treatment with methylhydrazine, the Pt(IV) bridge is reduced to the Pt(II) center, resulting in a Pt(II)-bridged cofacial dimer with a helicity inversion of the complex as well as change in electronic communication through the metal bridge.

Ten little indanones: The title reaction (see scheme; Si=trialkylsilyl) is proposed to go through a pathway involving a β‐carbon elimination/carborhodation sequence. Ready access to the carbinol substrates from an aromatic ester and a terminal alkyne makes the present catalysis reaction an efficient way of preparing 3‐alkynyl‐1‐indanones.