A Phase 1 Ascending Single and Multiple Oral Dose Study to Assess the Safety and Tolerability, Including Gastrointestinal Safety, Pharmacokinetics and Pharmacodynamics of ASP7657 in Caucasian Healthy Male and Female Subjects, Including a Food Effect Cohort

The purpose of this study is to evaluate the safety and tolerability of single and multiple ascending oral doses of ASP7657 in healthy subjects.

Start Date01 Apr 2014

Sponsor / Collaborator

Astellas Pharma Europe Ltd.

100 Clinical Results associated with ASP-7657

100 Translational Medicine associated with ASP-7657

100 Patents (Medical) associated with ASP-7657

Literatures (Medical) associated with ASP-7657

01 Jan 2023·BioMed Research International

Blockade of EP4 by ASP7657 Modulates Myeloid Cell Differentiation In Vivo and Enhances the Antitumor Effect of Radiotherapy

Article

Author: Nishibata, Toshihide ; Tsujimoto, Susumu ; Konagai, Satoshi ; Kawashima, Tomoko ; Tanaka-Kado, Ruriko ; Amino, Nobuaki ; Takeuchi, Masahiro ; Suzuki, Tomoyuki

The tumor microenvironment (TME) is thought to influence the antitumor efficacy of immuno‐oncology agents through various products of both tumor and stromal cells. One immune‐suppressive factor is prostaglandin E2 (PGE2), a lipid mediator whose biosynthesis is regulated by ubiquitously expressed cyclooxygenase‐ (COX‐) 1 and inducible COX‐2. By activating its receptors, PGE2 induces immune suppression to modulate differentiation of myeloid cells into myeloid‐derived suppressor cells (MDSCs) rather than dendritic cells (DCs). Pharmacological blockade of prostaglandin E receptor 4 (EP4) causes a decrease in MDSCs, reprogramming of macrophage polarization, and increase in tumor‐infiltrated T cells, leading to enhancement of antitumor immunity in preclinical models. Here, we report the effects of the highly potent EP4 antagonist ASP7657 on the DC population in tumor and antitumor immune activation in an immunocompetent mouse tumor model. Oral administration of ASP7657 inhibited tumor growth, which was accompanied by an increase in intratumor DC and CD8+ T cell populations and a decrease in the M‐MDSC population in a CT26 immunocompetent mouse model. The antitumor activity of ASP7657 was dependent on CD8+ T cells and enhanced when combined with an antiprogrammed cell death‐1 (PD‐1) antibody. Notably, ASP7657 also significantly enhanced the antitumor efficacy of radiotherapy in an anti‐PD‐1 antibody refractory model. These results indicate that the therapeutic potential of ASP7657 arises via upregulation of DCs and subsequent CD8+ T cell activation in addition to suppression of MDSCs in mouse models and that combining EP4 antagonists with radiotherapy or an anti‐PD‐1 antibody can improve antitumor efficacy.

01 Apr 2019·Naunyn-Schmiedeberg's Archives of Pharmacology

Renoprotective effects of the novel prostaglandin EP4 receptor-selective antagonist ASP7657 in 5/6 nephrectomized chronic kidney disease rats

Article

Author: Nozawa, Eisuke ; Wada, Koichi ; Ugawa, Tohru ; Mizukami, Kazuhiko ; Yoshida, Hiroyuki

Prostaglandins (PGs) are important lipid mediators of numerous physiologic and pathophysiologic processes in the kidney. PGE₂, the most abundant renal PG, plays a major role in renal physiology, including renin release and glomerular hemodynamics. We investigated the renoprotective properties of the novel PGE₂ EP4 receptor-selective antagonist ASP7657 in 5/6 nephrectomized rats, a chronic kidney disease (CKD) model. Eight weeks of repeated administration of ASP7657 (0.001-0.1 mg/kg) dose-dependently and significantly reduced urinary protein excretion and attenuated the development of glomerulosclerosis and tubulointerstitial damage, including fibrosis and inflammatory cell infiltration, without affecting blood pressure. Additionally, ASP7657 tended to have beneficial effects on renal function, as indicated by the decrease in plasma creatinine and blood urea nitrogen levels and attenuation of the decline in creatinine clearance (Ccr). The angiotensin II receptor blocker losartan (10 mg/kg) also showed these renoprotective effects while significantly reducing blood pressure. ASP7657 dose-dependently and significantly reduced the EP4 receptor agonist-induced increase in plasma renin activity, as assessed by angiotensin I release in normal rats. Additionally, ASP7657 attenuated hyperfiltration assessed by Ccr without changing the renal blood flow or blood pressure in diabetic rats. These results suggest that ASP7657 suppresses the progression of chronic renal failure by modulating renin release and improving renal hemodynamics, and may therefore be a promising therapeutic option for inhibiting the progression of CKD.

01 Dec 2018·Naunyn-Schmiedeberg's Archives of PharmacologyQ4 · MEDICINE

Pharmacological properties of ASP7657, a novel, potent, and selective prostaglandin EP4 receptor antagonist

Q4 · MEDICINE

Article

Author: Yoshida, Hiroyuki ; Kamada, Hiroaki ; Ishii, Ikuko ; Ugawa, Tohru ; Mizukami, Kazuhiko ; Wada, Koichi ; Nozawa, Eisuke

We determined the pharmacologic profile of ASP7657, trans-4-[({[1-(quinolin-2-ylmethyl)-5-(trifluoromethyl)-1H-indol-7 yl] carbonyl} amino) methyl] cyclohexanecarboxylic acid methanesulfonate (1:1), a newly synthesized selective E-type prostaglandin (EP)4 receptor antagonist using several in vitro and in vivo experiments. ASP7657 exhibited high affinity for rat and human EP4 receptors, with K_i values of 6.02 nM and 2.21 nM, respectively. In addition, ASP7657 potently inhibited the PGE₂-induced cyclic adenosine monophosphate (cAMP) increase in Chinese hamster ovary (CHO) cells expressing rat EP4 receptors and human lymphoblastoid T (Jurkat) cells, with IC₅₀ values of 0.86 nM and 0.29 nM, respectively. In contrast, ASP7657 did not inhibit the PGE₂-induced intracellular calcium increase in HEK293 cells expressing rat EP1 and EP3 receptors, or cAMP increase in CHO cells expressing rat EP2 receptors. ASP7657 showed good pharmacokinetic properties following oral dosing and dose-dependently antagonized the prostaglandin (PG)E₂-mediated inhibition of lipopolysaccharide-induced tumor necrosis factor-α release from rat whole blood culture. In addition, 4 weeks repeated oral administration of ASP7657 dose-dependently attenuated albuminuria in type 2 diabetic mice; these effects were significant at doses of 0.01 mg/kg or higher. These results demonstrate that ASP7657 is a potent and selective EP4 receptor antagonist that may be useful in future studies to help clarify the physiological and pathophysiological roles of PG.

100 Deals associated with ASP-7657

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