Osteoarthritis
(OA) is a degenerative disease characterized by
joint destruction and loss of cartilage. There are many unmet needs
in the treatment of OA and there are few promising candidates for
disease-modifying OA drugs, particularly, anabolic agents. Here, we
describe the identification of novel quinazolin-4(3H)-one derivatives, which stimulate chondrocyte cartilage matrix production
via TRPV4 and mitigate damaged articular cartilage. We successfully
identified the water-soluble, highly potent quinazolin-4(3H)-one derivative 36 and studied its intra-articular
physicochemical profile to use in in vivo surgical OA model studies.
Compound 36·HCl provided relief from
OA damage in a rat medial meniscal tear (MT) model. Specifically, 36·HCl dose-dependently suppressed cartilage degradation
and enhanced the messenger RNA expression of aggrecan and SOX9 in
cartilage isolated from MT-operated rat knees compared with knees
treated with vehicle. These results suggest that 36 induces
anabolic changes in articular cartilage and consequently reduces OA
progression.
The goal of the reconstruction for umbilical absence is to obtain a natural three-dimensional appearance of the umbilicus with minimal operative scarring. This paper presents two cases of umbilical reconstruction using a reverse fan-shaped flap. In both cases, the umbilicus was lost during surgical procedures on the abdominal wall when the patients were newborns. We performed this technique in both cases. This technique is simple and safe. With this technique, a permanent umbilical depth and ring can be obtained without any complications.
Two
chemical series of novel protein kinase C ζ (PKCζ)
inhibitors, 4,6-disubstituted and 5,7-disubstituted isoquinolines,
were rapidly identified using our fragment merging strategy. This
methodology involves biochemical screening of a high concentration
of a monosubstituted isoquinoline fragment library, then merging hit
isoquinoline fragments into a single compound. Our strategy can be
applied to the discovery of other challenging kinase inhibitors without
protein–ligand structural information. Furthermore, our optimization
effort identified the highly potent and orally available 5,7-isoquinoline 37 from the second chemical series. Compound 37 showed good efficacy in a mouse collagen-induced arthritis model.
The in vivo studies suggest that PKCζ inhibition is a novel
target for rheumatoid arthritis (RA) and that 5,7-disubstituted isoquinoline 37 has the potential to elucidate the biological consequences
of PKCζ inhibition, specifically in terms of therapeutic intervention
for RA.
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