Kazuhiro Kosakai

Discovery of Ipragliflozin (ASP1941): a novel C-glucoside with benzothiophene structure as a potent and selective sodium glucose co-transporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes mellitus.

A series of C-glucosides with various heteroaromatics has been synthesized and its inhibitory activity toward SGLTs was evaluated. Upon screening several compounds, the benzothiophene derivative (14a) was found to have potent inhibitory activity against SGLT2 and good selectivity versus SGLT1. Through further optimization of 14a, a novel benzothiophene derivative (14h; ipragliflozin, ASP1941) was discovered as a highly potent and selective SGLT2 inhibitor that reduced blood glucose levels in a dose-dependent manner in diabetic models KK-A(y) mice and STZ rats.

Pharmacological properties of KT3-671, a novel nonpeptide angiotensin II receptor antagonist.

We examined pharmacological profiles of KT3–671, 2-propyl-8-oxo-l-[(2‘-(lH-tetrazole-5-yl) biphe-nyl-4-yl)methyl]-4,5,6,7-tetrahydro-cycloheptimidazole, a newly synthesized nonpeptide angiotensin II (AII) receptor antagonist in various in vitro and in vivo studies. KT3–671 displaced specific binding of [125I]Sar1 Ile8-AII to AT1 receptor with a Ki value of 0.71 ± 0.14 x 10-9M in rat liver membranes, but had no affinity for AT2 receptor in bovine cerebellar membranes (Ki > 10-5M). In isolated rabbit aorta, KT3–671 produced a parallel right-ward shift in the concentration-response curve for AH with a pA2 value of 10.04 ± 0.12, but had no effect on K.CI-, norepinephrine (NE)-, and serotonin (5-HT)-induced contractions. In conscious normotensive rats, KT3–671 (0.3–10 mg/kg, p.o.) inhibited the All-induced pressor response dose dependently. In renal arteryligated hypertensive rats, KT3–671 (0.1–3 mg/kg, p.o.) decreased arterial blood pressure (BP) dose dependently. The hypotensive action of 3 mg/kg KT3–671 was maintained for at least 24 h. These results suggest that KT3–671 is a potent AT1 subtype-selective and competitive nonpeptide AII receptor antagonist and has an orally active antihypertensive effect without agonistic activity.

Synthesis and biological evaluation of C-glucosides with azulene rings as selective SGLT2 inhibitors for the treatment of type 2 diabetes mellitus: discovery of YM543.

Here, a series of C-glucosides with azulene rings in the aglycon moiety was synthesized and the inhibitory activities toward hSGLT1 and hSGLT2 were evaluated. Starting from the azulene derivative 7 which had relatively good SGLT2 inhibitory activity, compound 8a which has a 3-[(azulen-2-yl)methyl]phenyl group was identified as a lead compound for further optimization. Introduction of a phenolic hydroxyl group onto the central benzene ring afforded a potent and selective SGLT2 inhibitor 8e, which reduced blood glucose levels in a dose-dependent manner in rodent diabetic models. A mono choline salt of 8e (YM543) was selected as a clinical candidate for use in treating type 2 diabetes mellitus.

Azulene derivatives as TXA2/PGH2 receptor antagonists--II. Synthesis and biological activity of 6-mono- and 6-dihydroxylated-isopropylazulenes.

In order to examine the correlation between activity and hydrophilicity of the side chain of sodium 3-[4-(4-chlorobenzenesulfonylamino)butyl]-6-isopropylazulene -1-sulfonate (KT2-962), a non-prostanoid TXA2/PGH2 receptor antagonist, one or two hydroxyl groups were introduced into the isopropyl moiety. A series of 6-hydroxylated-isopropylazulenes were synthesized by regioselective oxidation of 6-isopropylazulenes and their in vitro and in vivo antagonistic activities were studied. Both the primary and tertiary alcohols, monohydroxylated derivatives, exhibited potent biological activities comparable to unmodified 6-isopropylazulenes both in vitro and in vivo. In contrast, the activities of 1,2- and 1,3-diols of 6-substituted derivatives, markedly decreased, but recovered by O-isopropylidenation of the dihydroxyl moiety. These findings indicate that the moderate hydrophobicity of substituent at the 6-position of the azulene ring might be required for the activity and the size of the substituent at this position, not so rigid for keeping potent biological activity.

Pharmacologic properties of KT2-962 (6-isopropyl-3-[4-(p- chlorobenzenesulfonylamino)-butyl]-azulene-1-sulfonic acid sodium salt); a new TXA2/prostaglandin endoperoxide receptor antagonist.

Pharmacologic properties of KT2–962 (6-iso-propyl-3-[4-(p-chlorobenzenesulfonylamino)butyl]-azu-lene-1-sulfonic acid sodium salt, KT) were studied in isolated rat aorta, rat tail artery, rabbit aorta, rabbit renal artery, and pig coronary artery. KT competitively inhibited the contractions induced by thromboxane A2 (TXA2) mimetic, U46619 (pA2 values 9.95, 8.85, 7.87, 8.49, and 9.12, respectively). KT also inhibited the contraction of rabbit aorta induced by prostaglandin2α, (PGF2α, pA2 value 7.85) and the contraction of guinea pig ileum induced by LTD4 (pA2 value 5.48) but did not alter the contractions induced by norepinephrine (NE). Ca2+, serotonin, and histamine. KT did not alter the contractions of guinea pig ileum, which did not contract with U46619, induced by PGE2 and PGF2α, KT inhibited the aggregations of rabbit platelets induced by U46619, arachidonic acid, and collagen (IC50 values 7.9, 140, and 16 μM, respectively) but not those induced by ADP. It also inhibited the specific binding of TXA2/PGH2 receptor antagonist, [3H]SQ29,548, to rabbit gel-filtered platelets with an IC50 value of 1.5 × 10-8 M. In in vivo experiments with mice, oral administration of KT protected the U46619-induced sudden death with the minimum effective dose of 0.3 mg/kg and provided such protection for ≥8 h at 1.0 mg/kg. These results indicate that KT is a new nonpros-tanoid type TXA2/PGH2 receptor antagonist that is orally effective and long acting.

Vasoinhibitory action of KT2-734, an antihypertensive agent, in isolated rat aorta

In rat aorta, KT2-734 inhibited contractile responses to 5-hydroxytryptamine (5-HT) and KCl. KT2-734 inhibited the relaxing effect of verapamil, but not nifedipine. Similarly, verapamil, but not nifedipine, inhibited the vasorelaxing effect of KT2-734. KT2-734 relaxation was inhibited by endothelium removal but not by atropine and propranolol. Methylene blue, a guanylyl cyclase inhibitor, and NG-monomethyl arginine also inhibited the relaxation both in the presence and absence of endothelium. In the absence of endothelium, KT2-734 potentiated the relaxation induced by L-arginine, nitroglycerin and isoproterenol. In addition, M & B 22,948, a cGMP phosphodiesterase inhibitor, and theophylline inhibited and potentiated, respectively, KT2-734-induced relaxation. However, methylene blue inhibited the potentiation of isoproterenol relaxation by KT2-734 and that of KT2-734-relaxation by theophylline. KT2-734 caused increases in the level of cGMP without significantly affecting the cAMP level. These results suggest that KT2-734 may cause endothelium-independent relaxation mainly due to inhibition of cGMP-phosphodiesterase.

Role of sulfonamide moiety in non-prostanoid txa2 receptor antagonist kt2-962 : modifications of this moiety and the resulting activities

Abstract Modification of sulfonamide moiety in non-prostanoid thromboxane A 2 (TXA 2 ) receptor antagonist, KT2-962 with double amide, sulfonamide-amide, (thio)semicarbazone, inverse sulfonamide and N-sulfonylcarboxamide is described. Unlike prostanoid TXA 2 antagonists, the importance of sulfonamide moiety for the activity of non-prostanoid TXA 2 receptor antagonist, KT2-962 was confirmed.

Characterization of the vasoinhibitory actions of KT2-230, a new benzothiazepine vasodilator derivative on isolated rabbit vascular smooth muscles: An alpha-adrenergic- and serotonergic-receptor antagonist

1. Pharmacological properties of KT2-230 (benzothiazepine derivative), a newly synthesized vasorelaxing agent, were studied. 2. In the anesthetized dogs, KT2-230 increased the femoral and vertebral blood flow without effect on systemic blood pressure. 3. In rabbit aorta, KT2-230, methysergide and phentolamine inhibited contractile responses to 5-hydroxytryptamine. 4. The response to norepinephrine was also inhibited by KT2-230 and phentolamine. Responses to histamine were not affected by KT2-230. 5. Responses to KCl and Ca2+ in K+ depolarized aorta in Ca2(+)-free medium were inhibited by a high concentration of KT2-230. 6. In rabbit iliac artery, KT2-230 inhibited the response to caffeine in Ca2(+)-free medium. 7. KT2-230 decreased total La3(+)-resistant Ca2(+)-binding at high affinity sites. 8. These results indicate that KT2-230 inhibits alpha 1-adrenoceptors and 5-HT-receptors and at high concentrations it inhibits slow Ca2(+)-channels. KT2-230 may inhibit the Ca2(+) release from caffeine- and agonist-sensitive Ca2+ stores.