Takenori Ishizawa

Novel hyaluronic acid-methotrexate conjugates for osteoarthritis treatment.

Hyaluronic acid (HA) provides synovial fluid viscoelasticity and has a lubricating effect. Injections of HA preparations into the knee joint are widely used as osteoarthritis therapy. The current HA products reduce pain but do not fully control inflammation. Oral methotrexate (MTX) has anti-inflammatory efficacy but is associated with severe adverse events. Based on the rationale that a conjugation of HA and MTX would combine the efficacy of the two clinically evaluated agents and avoid the risks of MTX alone, we designed HA-MTX conjugates in which the MTX connects with the HA through peptides susceptible to cleavage by lysosomal enzymes. Intra-articular injection of our HA-MTX conjugate (conjugate 4) produced a significant reduction of the knee swelling in antigen-induced arthritis rat, whereas free MTX, HA or a mixture of HA and MTX showed no or marginal effects on the model. The efficacy of conjugate 4 was almost the same as that of MTX oral treatment. Conjugate 4 has potential as a compound for the treatment of osteoarthritis.

Design of potent K+ channel openers by pharmacophore model

Abstract A pharmacophore model which explains rationally structure-activity relationships of chemically diverse potent K + channel openers, has been constructed. Potent benzopyran derivatives with thioamide, amide, and ( N -cyano)amidine groupa at the 4-position have been designed using the model.

Synthesis and optimization of hyaluronic acid-methotrexate conjugates to maximize benefit in the treatment of osteoarthritis.

We previously reported that a conjugate of hyaluronic acid (HA) and methotrexate (MTX) could be a prototype for future osteoarthritis drugs having the efficacy of the two clinically validated agents but with a reduced risk of the systemic side effects of MTX by using HA as the drug delivery carrier. To identify a clinical candidate, we attempted optimization of a lead, conjugate 1. Initially, in fragmentation experiments with cathepsins, we optimized the peptide part of HA-MTX conjugates to be simpler and more susceptible to enzymatic cleavage. Then we optimized the peptide, the linker, the molecular weight, and the binding ratio of the MTX of the conjugates to inhibit proliferation of human fibroblast-like synoviocytes in vitro and knee swelling in rat antigen-induced monoarthritis in vivo. Consequently, we found conjugate 30 (DK226) to be a candidate drug for the treatment of osteoarthritis.

N,N-disubstituted benzopyran-4-(N′-cyano)carboxamidines, cromakalim analogs with selective activity for guinea pig trachealis

N-Cyano-2,2-dimethyl-6-nitro-2H-1-benzopyran-4-carboxamidines have been synthesized. Some of these compounds exhibited selective activity for guinea pig trachealis.

6-Substituted 2,2-bis(fluoromethyl)-benzopyran-4-carboxamide K+ channel openers.

In the course of our study to find an ideal antihypertensive potassium channel opener (KCO), N-(2-cyanoethyl)-2,2-bis(fluoromethyl)-6-pentafluoroethyl-2H-1-ben zopyran-4-carboxamide (13f, KC-515) showed a highly potent, slow and long-lasting antihypertensive effect with reduced reflex tachycardia, together with the beneficial effects of KCO such as improvement in lipid metabolism. These profiles identify KC-515 as a potential candidate. In conscious spontaneously hypertensive rats (SHR), the onset of the hypotensive effect of KC-515 (13f) was gradual and the maximum response was attained at around 6 h after dosing. The duration of action was over 18 h for 0.1 mg/kg. When administered to Zucker rats for 2 weeks with 0.03-0.3 mg/kg po range in the antihypertensive doses in hypertensive rat models, KC-515 (13f) significantly and dose-dependently reduced serum triglycerides to less than 70% of control without affecting total cholesterol.

Benzopyran-4-carboxamide K+ channel openers

Abstract N -Substituted benzopyran-4-carboxamides 5 have been synthesized. Some of these compounds exhibited potent vasorelaxant activity.

Synthesis and antihypertensive activity of KC-399, a benzopyran K+ channel opener with long duration of action and less tachycardia

Abstract Synthesis and antihypertensive activity of KC-399 (5) have been described. KC-399 (5) showed a highly potent, slow and long-lasting antihypertensive effect with reduced reflex tachycardia.

Structure-activity relationships of 6-substituted benzopyran-4-carbothioamide potassium channel openers.

Abstract QSAR study of 6-substituted benzopyran-4-carbothioamides 1 showed that vasorelaxant activity is linearly correlated with the electronic parameter (σ m ) and parabolically correlated with steric ( L ) and hydrophobic (π) parameters of the 6-substituent.

Synthesis of key intermedia tes benzopyran-4-carboxylic acids of new potassium channel openers benzopyran-4-amides via palladium-catalyzed hydroxycarbonylation

Abstract Key intermediates benzopyran-4-carboxylic acids of an important class of potassium channel openers benzopyran-4-amides have been synthesized via palladium-catalyzed hydroxycarbonylation.

Vasorelaxant activity of 2-fluoroalkyl-6-nitro-2H-1-benzopyran-4-carbothioamide and -carboxamide K+ channel openers

Abstract Synthesis and vasorelaxant activity of 2-fluoroalkyl-6-nitro-2 H -1-benzopyran-4-carbothioamides 4 and 6 and -carboxamides 5 and 7 are described. Potent smooth muscle relaxant activity was displayed by 6c .