[Pharmacological profile and clinical efficacy of imeglimin hydrochloride (TWYMEEGTablets), 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 β-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 Ca under high-glucose conditions.

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

Starting with a subtle blood glucose-lowering effect of a TGF-β 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.

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.

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.

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.

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.

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.

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.

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.

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.