Successful treatment with bortezomib for refractory cryoglobulinemic vasculitis triggered by ischemic non-obstructive coronary artery disease.

Type I and mixed cryoglobulinemic vasculitis differ in pathophysiology, clinical presentation, and therapeutic response. We report a case of refractory cryoglobulinemic vasculitis diagnosed following ischemic non-obstructive coronary artery disease (INOCA). The patient presented with dyspnea, as well as abdominal pain due to ischemic enteritis, purpura, and renal failure requiring dialysis.

Mechanism of retinoid X receptor partial agonistic action of 1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1H-benzotriazole-5-carboxylic acid and structural development to increase potency.

We have reported that retinoid X receptor (RXR) partial agonist 1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1H-benzotriazole-5-carboxylic acid (CBt-PMN, 4a) shows a significant antidiabetes effect in the KK-A(y) type 2 diabetes model mice, with reduced side effects compared to RXR full agonists. To elucidate the mechanism of the RXR partial agonist activity of 4a, we synthesized derivatives of 4a, evaluated their RXR agonist activity, and performed structure-activity relationship analysis. Reporter gene assay revealed that though 6b, which possesses an amino group at the 2-position of 5-carboxybenzimidazole, showed RXR full-agonist activity, compounds 6d and 6e, which possess an oxygen atom and a sulfur atom at the corresponding position, respectively, showed weak RXR agonist activity.

RXR Partial Agonist CBt-PMN Exerts Therapeutic Effects on Type 2 Diabetes without the Side Effects of RXR Full Agonists.

Treating insulin resistance and type 2 diabetes in rodents, currently known retinoid X receptor (RXR) agonists induce significant adverse effects. Here we introduce a novel RXR partial agonist CBt-PMN (11b), which shows a potent glucose-lowering effect and improvements of insulin secretion and glucose tolerance without the serious adverse effects caused by RXR full agonists. We suggest that RXR partial agonists may be a new class of antitype 2 diabetes drug candidates.

Discovery of a Potent Retinoid X Receptor Antagonist Structurally Closely Related to RXR Agonist NEt-3IB.

We discovered a potent retinoid X receptor (RXR) antagonist, 6-[N-ethyl-N-(5-isobutoxy-4-isopropyl-2-(E)-styrylphenyl)amino]nicotinic acid (13e), that is structurally closely related to the RXR full agonist 6-[N-ethyl-N-(3-isobutoxy-4-isopropylphenyl)amino]nicotinic acid (NEt-3IB) (4). Compound 13e was synthesized via a simple route from 11, a methyl ester precursor of 4. Because 11 possesses high electrophilic reactivity because of the amino and alkoxy groups, it was readily transformed to 12 by iodization, and the iodine atom of 12 was converted to a C-C or C-N bond by means of palladium-catalyzed reaction to afford 13.

Kinetic isotope effect of the L-phenylalanine oxidase from Pseudomonas sp. P-501.

Pseudomonas L-phenylalanine oxidase (deaminating and decarboxylating) mainly catalyzes oxygenation when L-phenylalanine is used as the substrate, but oxidation when L-methionine is used as the substrate. Using [C(alpha)-H]-DL-methionine and [C(alpha)-D]-DL-methionine as substrate, the reductive half reaction of FAD cofactor of enzyme has been studied by stopped-flow spectrophotometry. The rate of reduction of FAD cofactor has a kinetic isotope effect (KIE) of 5.