[Pharmacological profile and clinical efficacy of imeglimin hydrochloride (TWYMEEG®Tablets), the orally drug for type 2 diabetes mellitus with the first dual mode of action in the world].

Imeglimin hydrochloride (imeglimin) is an orally drug for type 2 diabetes mellitus, which was approved in Japan for the first in the world, with dual mode of actions: pancreatic action means amplifying glucose-stimulated insulin secretion (GSIS) in pancreatic ß-cells, and extrapancreatic action means improving insulin sensitivity by which gluconeogenesis suppresses in hepatocytes and glucose uptake increases in skeletal muscles. Although the molecular target of imeglimin is still unknown, imeglimin exerts some of its actions through modulation of the mitochondrial function. In pancreatic islets, imeglimin enhanced adenosine triphosphate and Ca2+ under high-glucose conditions. Furthermore, imeglimin induced the synthesis of oxidized form nicotinamide adenine dinucleotide (NAD+) via the 'salvage pathway', and NAD+ metabolites may contribute to the increase in intracellular Ca2+. The in vivo studies indicated that imeglimin enhanced the sensitivity to insulin and modulated the mitochondrial function (restoring the deficient Complex III activity, decreasing Complex I activity and reactive oxygen species production), which contribute to the improvement of glucose metabolism in hepatocytes and skeletal muscles. In clinical trials, imeglimin's dual effects were demonstrated in foreign type 2 diabetic patients who received 1500 mg bid, which is different from the domestic approved dose. Imeglimin has been shown to evidence of statistically significant glucose lowering, a generally favorable safety and tolerability profile in patients with type 2 diabetes by monotherapy and combination therapy with 1,000 mg bid in four Japanese trials. Since imeglimin has dual effects, it may have shown a newly effective option, regardless of the pathophysiology of type 2 diabetic patients.

Development of a new class of benzoylpyrrole-based PPARα/γ activators.

Starting with a subtle blood glucose-lowering effect of a TGF-ß inhibitor, we designed and synthesized a series of benzoylpyrrole-based carboxylic acids as PPARs activators. Among these compounds, 10sNa exhibited favorable blood glucose-lowering effect without body weight gain. We assume that the beneficial effect of 10sNa is attributed to not only its compound PPARα agonistic activity but also its PPARγ partial agonistic activity.

Combination therapy with SMP-534 and an angiotensin-converting enzyme inhibitor provides additional renoprotection in 5/6 nephrectomized rats.

The number of patients with chronic kidney disease (CKD) has continuously grown worldwide. Treatment with antihypertensive agents reduces the rate of progression of CKD, however, there is still a large unmet need to develop strategies for the treatment of CKD. Although we have previously reported that the antifibrotic agent, SMP-534 inhibits the progression of CKD, it is unknown whether combination therapy with SMP-534 and antihypertensive agent shows additive effects on CKD. In present study, we examined whether combination therapy with SMP-534 and the antihypertensive agent, lisinopril is more effective than single therapy with SMP-534 or lisinopril on five-sixths nephrectomized (5/6Nx) rat model. Combination therapy with SMP-534 (50 mg/kg) and lisinopril (5 mg/kg) significantly decreased urinary albumin excretion, blood urea nitrogen (BUN) and serum creatinine and increased creatinine clearance in 5/6Nx rats. On the other hands, single treatment with SMP-534 or lisinopril did not improve renal function at this dose. In addition, combination therapy with SMP-534 and lisinopril significantly decreased extracellular matrix (ECM) accumulation in renal glomeruli and tubulointerstitial injury. These data suggest that combination therapy with an antifibrotic agent and an antihypertensive agent may offer a new therapeutic option for suppressing the progression of CKD.

The anti-fibrotic agent SMP-534 attenuates bleomycin-induced pulmonary fibrosis in hamsters.

Pulmonary fibrosis is a progressive and lethal lung disease characterized by accumulation of ECM and loss of pulmonary function. However, no cure exists for this disease, and current treatments often fail to slow its progression or relieve its symptoms. We have previously reported that the anti-fibrotic agent SMP-534 has beneficial effects on renal fibrosis in animal model of nephropathy. In this study, we examined whether SMP-534 has beneficial effects on pulmonary fibrosis in bleomycin-treated hamsters. Treatment with SMP-534 [low dose (70 mg/kg) or high dose (110 mg/kg)] counteracted inhibition of body weight increase induced by bleomycin. In addition, SMP-534 significantly inhibited bleomycin-induced increase in lung hydroxyproline level, an index of collagen formation. Moreover, SMP-534 significantly ameliorated histological pulmonary fibrotic changes induced by bleomycin. The results of this study indicate that the anti-fibrotic agent SMP-534 may offer a new therapeutic option for the treatment of pulmonary fibrosis.

Chronic administration of SMP-534 ameliorates renal dysfunction in 5/6 nephrectomized rats.

BACKGROUND/AIMS: Chronic kidney disease (CKD) is the common cause of end-stage renal disease. Antihypertensive agents are clinically used to inhibit the progression of CKD. However, these agents cannot completely prevent progression to renal failure. We have previously reported that 5-chloro-2-{(1E)-3-[2-(4-methoxybenzoyl)-4-methyl-1H- pyrrol-1-yl]prop-1en-1-yl}-N-(methylsulfonyl)benzamide (SMP-534) improves renal disease and prevents the production of extracellular matrix in vitro. Additionally, SMP-534 inhibits glomerular fibrosis and provides renoprotection in vivo. In the present study, we investigated the effect of SMP-534 on renal dysfunction in a 5/6 nephrectomized (5/6Nx) rat model. METHOD: Five groups of rats were studied: sham operated, 5/6Nx + vehicle, 5/6Nx + SMP-534 30 mg/kg, 5/6Nx + SMP-534 60 mg/kg and 5/6Nx + SMP-534 90 mg/kg. Treatment with SMP-534 began 13 weeks after surgery, when hypertension and renal insufficiency had developed. Serum creatinine, blood urea nitrogen levels, creatinine clearance and urinary albumin were measured at specific time points. RESULTS: Serum creatinine and blood urea nitrogen levels were significantly reduced in SMP-534-treated groups. In addition, SMP-534 dose-dependently suppressed the increase in urinary albumin excretion observed in 5/6Nx rats. Moreover, survival rates were improved in SMP-534-treated groups. CONCLUSION: We have shown in this study that chronic oral administration of SMP-534 improves renal dysfunction in 5/6Nx rats. These findings indicate that SMP-534 may be a new therapeutic agent for the treatment of CKD.

Amelioration of established diabetic nephropathy by combined treatment with SMP-534 (antifibrotic agent) and losartan in db/db mice.

BACKGROUND/AIMS: Diabetic nephropathy is the main cause of end-stage renal disease. Previously we have demonstrated that SMP-534 (an antifibrotic agent) prevents the development of diabetic nephropathy in db/db mouse and that combined treatment with SMP-534 and losartan (antihypertensive agents) markedly prevents the development of diabetic nephropathy compared with single treatment. SMP-534 or losartan was prophylactically administered to db/db mice before the onset of diabetic nephropathy. In the present study, we evaluated the efficacy of combined treatment when administration was started after the onset of diabetic nephropathy. METHODS: db/db mice were raised untreated until 17 weeks of age, by which time increase of urinary albumin was noted, and then treated with SMP-534 and/or losartan for another 8 weeks. Biochemical and histological analyses were performed at 25 weeks of age. RESULTS: Combined treatment with SMP-534 and losartan markedly prevented the increase of urinary albumin and ameliorated the progression of mesangial matrix expansion, even when administration was started long after the increase of urinary albumin. CONCLUSION: The study results indicate that a combination of SMP-534 and losartan might be a valuable therapeutic approach for the treatment of diabetic nephropathy even when administration is started after the onset of diabetic nephropathy.

Recombinant human growth hormone (SMP-140) is effective for growth promotion in hypophysectomized rats.

Growth hormone (GH) replacement therapy has been shown to have beneficial effects on linear growth enhancement in GH-deficient children over the past few decades. SMP-140 is a sterile liquid formation containing rhGH that is expected to improve patient compliance and accuracy of dosing, compared with the commercially available lyophilized form of GH. However, since there are no data showing that SMP-140 influences body elongation in animal models, we studied the effects of SMP-140 on body length in hypophysectomized (HPX) rats, which are used as animal models of GH deficiency. Consistent with the main feature of GH-deficient children, the body length of HPX rats was significantly shorter than that of sham-operated rats at the start of the study. SMP-140 (0.2, 1 and 5 mg/kg) was administered once daily to HPX rats for seven days, and resulted in a dose-dependent increase in body length and in the width of the growth plate cartilage. These results show that SMP-140 administration increases body length in an animal model of GH deficiency, and suggest that SMP-140 will be a useful agent for the treatment of growth-retarded children.

Synthesis and pharmacological profile of an orally-active growth hormone secretagogue, SM-130686.

Hypothalamic hormones physiologically regulate pulsatile release of growth hormone (GH) from the anterior pituitary gland. Since the discovery of these hormones in the 1970s, several new chemically synthesized peptidyl and non-peptidyl derivatives have been proved to stimulate and amplify GH secretion, and this series of molecules has been named the growth hormone secretagogues (GHSs). One of these compounds led to the discovery of a GPCR-type receptor for GHSs (GHS-R), and subsequently the endogenous ligand for the receptor has been identified, and is referred to as ghrelin. The identification of GHSs as physiological regulators of GH secretion encouraged us to examine our GHSs pharmacologically. We previously reported that novel oxindole derivatives have been identified as GHS-R agonists from our internal chemical library. Among these derivatives, (+)-6-carbamoyl-3-(2-chlorophenyl)-(2-diethylaminoethyl)-4-trifluoromethyloxindole (SM-130686, 37S) was found to have potent activity in vitro with a good pharmacokinetic profile in rats (bioavailability of 28%). In this article, we review the synthesis and pharmacological evaluation of SM-130686. SM-130686 binds specifically to GHS-R and increases the Ca(2+) concentration in Chinese hamster ovary cells expressing recombinant GHS-R. Maximal enhancement of the intracellular Ca(2+) concentration induced by SM-130686 treatment was approximately 55% that induced by ghrelin, suggesting that SM-130686 may be a partial GHS-R agonist. Also, in in vivo studies, oral administration of SM-130686 increased body length and fat-free mass gain. We compare the pharmacological profile of SM-130686 with other GHSs, including GHRH and ghrelin, and discuss the therapeutic usefulness of GHSs against several disorders, as well as for treatment of GH deficiency.

Enhanced effect of combined treatment with SMP-534 (antifibrotic agent) and losartan in diabetic nephropathy.

BACKGROUND/AIMS: Diabetic nephropathy is now the most common cause of end-stage renal disease. It is also clear that the current therapy, angiotensin II blockage, cannot prevent the progression of diabetic nephropathy. We had previously demonstrated that an antifibrotic agent, SMP-534, reduced extracellular matrix production induced by transforming growth factor-beta in vitro, and that SMP-534 prevented renal fibrosis and urinary albumin in diabetic db/db mice via a nonantihypertensive mechanism. We expected that combined use of SMP-534 and losartan would produce a more highly renoprotective action. METHODS: We examined the effects of combined treatment with SMP-534 and losartan on urinary albumin and glomerular fibrosis in db/db mice. Diet containing these agents was provided from age 9 to 25 weeks. Blood and urine analyses were performed at 8, 17, and 25 weeks. At the end of the study, kidney tissues were histologically analyzed. RESULTS: SMP-534 significantly suppressed an increase in urinary albumin excretion and ameliorated the progression of glomerular fibrosis in db/db mice, whereas losartan did not. Combined treatment with SMP-534 and losartan markedly prevented the increase of urinary albumin excretion compared with treatment with either SMP-534 or losartan alone. In contrast, renal histological analysis revealed that combined treatment did not significantly prevent an increase of mesangial expansion in the kidney compared with treatment with SMP-534 alone. CONCLUSION: A combination of the two agents, SMP-534 and losartan, might be a valuable therapeutic approach for the treatment of diabetic nephropathy.

SMP-534 ameliorates progression of glomerular fibrosis and urinary albumin in diabetic db/db mice.

Diabetic nephropathy is currently the most common cause of end-stage renal disease. Diabetic nephropathy patients, whether insulin dependent or not, develop fibrotic changes in glomeruli that manifest as overt nephropathy. Previously, we demonstrated that 5-chloro-2-{(1E)-3-[2-(4-methoxybenzoyl)-4-methyl-1H-pyrrol-1-yl]prop-1-en-1-yl}-N-(methylsulfonyl)benzamide (SMP-534) reduces extracellular matrix (ECM) production induced by transforming growth factor-beta (TGF-beta) in vitro and prevents the accumulation of ECM in glomeruli in rat Thy-1 nephritis models. In this study, we examined the long-term effects of SMP-534 on renal insufficiency and glomerulosclerosis in db/db mice, which are models of type 2 diabetes. A diet containing SMP-534 was given to the mice from the age of 9 to 25 wk, and blood and urine analysis were performed at 8, 17, and 25 wk. At the end of study, kidney tissues were analyzed histologically. Treatment with SMP-534 dose dependently suppressed the increase of urinary albumin and type IV collagen excretion in db/db mice. The renal histological analysis showed that SMP-534 dose dependently suppressed the increase of mesangial expansion in the kidney. In the immunohistological analysis, fibronectin and type IV collagen expression were lower in SMP-534-treated db/db mice compared with vehicle-treated db/db mice. This study suggested that SMP-534 ameliorated the increase of ECM production in kidney of db/db mice, possibly through the inhibition of TGF-beta action. Hence, antifibrotic agents such as SMP-534 might be a new therapeutic option for the treatment of diabetic nephropathy.

Structure-activity relationships of the oxindole growth hormone secretagogues.

A series of substituted oxindole derivatives of SM-130686 was synthesized and evaluated as ghrelin receptor agonists. Modification of the substituents on the C3-aromatic part of the oxindole led to compounds with subnanomolar binding affinities. Compound 4i (IC(50)=0.02 nM) was orally active at low doses and showed in vivo activity when orally administered, 2 mg/kg twice a day for 4 days, as evidenced by significant body weight gain.