Richard Clark

Effects of the Combination of a Dipeptidyl Peptidase IV Inhibitor and an Insulin Secretagogue on Glucose and Insulin Levels in Mice and Rats

Several combination therapies have been tried for treating of type 2 diabetes to control more effectively fasting hyperglycemia and postprandial hyperglycemia. In this study, we have examined the effects of combining a novel, selective, and competitive dipeptidyl peptidase IV (DPP-IV) inhibitor, 3-but-2-ynyl-5-methyl-2-piperazin-1-yl-3,5-dihydro-4H-imidazo[4,5-d]pyridazin-4-one tosylate (E3024), with a representative of one of two types of insulin secretagogues, i.e., either glybenclamide (a sulfonylurea) or nateglinide (a rapid-onset/short-duration insulin secretagogue), on glucose and insulin levels in an oral glucose tolerance test (OGTT) using mice fed a high-fat diet. In addition, we have investigated the effects of these combinations on blood glucose levels in fasting rats. Two-way analysis of variance showed that the combination of E3024 and glybenclamide improved glucose tolerance additively and also caused a synergistic increase in insulin levels in the OGTT in mice fed a high-fat diet. In a similar way, the combination of E3024 and nateglinide ameliorated glucose tolerance additively and raised insulin levels additively. In fasting rats, coadministration of E3024 with glybenclamide or nateglinide treatment did not affect the glucose-lowering effects of the insulin secretagogues. Therefore, a DPP-IV inhibitor in combination with glybenclamide or nateglinide may be a promising option for the treatment of type 2 diabetes, and particularly, for controlling postprandial hyperglycemia in the clinic.

Selective tissue factor/factor VIIa Inhibitor, ER-410660, and its prodrug, E5539, have anti-venous and anti-arterial thrombotic effects with a low risk of bleeding.

INTRODUCTION Many anticoagulant drugs target factors common to both the intrinsic and extrinsic coagulation pathways, which may lead to bleeding complications. Since the tissue factor (TF)/factor VIIa complex is associated with thrombosis onset and specifically activates the extrinsic coagulation pathway, compounds that inhibit this complex may provide therapeutic and/or prophylactic benefits with a decreased risk of bleeding. MATERIALS AND METHODS The in vitro enzyme profile and anticoagulation selectivity of the TF/VIIa complex inhibitor, ER-410660, and its prodrug E5539 were assessed using enzyme inhibitory and plasma clotting assays. In vivo effects of ER-410660 and E5539 were determined using a TF-induced, thrombin generation rhesus monkey model; a stasis-induced, venous thrombosis rat model; a photochemically induced, arterial thrombosis rat model; and a rat tail-cut bleeding model. RESULTS ER-410660 selectively prolonged prothrombin time, but had a less potent anticoagulant effect on the intrinsic pathway. It also exhibited a dose-dependent inhibitory effect on thrombin generation caused by TF-injection in the rhesus monkey model. ER-410660 also reduced venous thrombus weights in the TF-administered, stasis-induced, venous thrombosis rat model and prolonged the occlusion time induced by arterial thrombus formation after vascular injury. The compound was capable of doubling the total bleeding time in the rat tail-cut model, albeit with a considerably higher dose compared to the effective dose in the venous and arterial thrombosis models. Moreover, E5539, an orally available ER-410660 prodrug, reduced the thrombin-anti-thrombin complex levels, induced by TF-injection, in a dose-dependent manner. CONCLUSION Selective TF/VIIa inhibitors have potential as novel anticoagulants with a lower propensity for enhancing bleeding.

Practical syntheses of the adhesion molecule inhibitor ER-49890 and its stereoisomer

Practical synthetic routes to anti-[3-(10H-pyrazino[2,3-b][1,4]-benzothiazin-8-ylmethyl)-3-azabicyclo[3.3.1]non-9-yl]acetic acid (ER-49890, 1) and its syn-isomer are reported. The anti-(3-azabicyclo[3.3.1]non-9-yl)acetic acid side chain (anti-12) was synthesized stereoselectively using Pd/C hydrogenation in the presence of HCl. The syn-isomer (syn-12) was concisely obtained by crystallization as its oxalic acid salt from a 1:1 mixture of anti- and syn-isomers. The 10H-pyrazino[2,3-b][1,4]benzothiazine core (7) was prepared from commercially available 4-chloro-3-nitrobenzyl alcohol (13) in four steps and good yield.

Effects of a novel PAF antagonist, E6123, on PAF-indnced biological responses

E6123 is a new member of the benzodiazepine class of PAF antagonists. Although it has similar activity in vitro to the two representative antagonists WEB2347 and Y24180, in vivo it is far more active than these compounds. Thus E6123 was effective in inhibiting dose-dependently PAF-induced bronchoconstriction when administered orally or intravenously (IC50 1.0 and 1.3 micrograms/Kg, respectively, at 3 hr), and had a minimum effective dose of 10 micrograms/Kg and 3 micrograms/Kg, respectively, against PAF-induced hematoconcentration and edema at 3 hr after oral administration. Furthermore, E6123 protects mice from PAF-induced death dose-dependently (ED50 7 micrograms/Kg at 3 hr). In conclusion, E6123 should prove valuable in pharmacological and clinical research into the roles of PAF, and in therapy of diseases such as asthma, in which PAF is assumed to play a pathological role.