Selective progesterone receptor modulators (SPRMs) represent a new class of progesterone receptor ligands. SPRMs exert clinically relevant tissue-selective progesterone agonist, antagonist, or mixed agonist/antagonist effects on various progesterone target tissues in vivo. Asoprisnil (J867) is the first SPRM to reach an advanced stage of clinical development for the treatment of symptomatic uterine fibroids and endometriosis. Asoprisnil belongs to the class of 11beta-benzaldoxime-substituted estratrienes that exhibit partial progesterone agonist/antagonist effects with high progesterone receptor specificity in animals and humans. Asoprisnil has no antiglucocorticoid activity in humans at therapeutic doses. It exhibits endometrial antiproliferative effects on the endometrium and breast in primates. Unlike progesterone antagonists, asoprisnil does not induce labor in relevant models of pregnancy and parturition. It induces amenorrhea primarily by targeting the endometrium. In human subjects with uterine fibroids, asoprisnil suppressed both the duration and intensity of uterine bleeding in a dose-dependent manner and reduced tumor volume in the absence of estrogen deprivation. In subjects with endometriosis, asoprisnil was effective in reducing nonmenstrual pain and dysmenorrhea. Asoprisnil may, therefore, provide a novel, tissue-selective approach to control endometriosis-related pain. SPRMs have the potential to become a novel treatment of uterine fibroids and endometriosis.

G-protein-coupled receptor 40 (GPR40; free fatty acid (FFA) receptor 1) is a receptor for endogenous medium-and long-chain FFAs and is preferentially expressed in β-cells. [1][2][3] Activation of GPR40 by FFAs or synthetic ligands results in enhanced insulin secretion in the presence of increasing glucose concentrations, 1 suggesting that these compounds have the potential to be used as novel insulinotropic agents associated with reduced hypoglycemic risk. 4,5 TAK-875 is a highly selective, potent GPR40 agonist 6 with >400-fold stronger agonist activity than oleic acid in vitro. 7 In dose-ranging studies in healthy subjects, 8,9 TAK-875 was rapidly absorbed (time to peak plasma concentration (T max ) of 3-4 h) with a terminal elimination half-life (t 1/2 ) of ~28-30 h. The values of apparent volume of distribution and steady-state oral clearance (CL/F) were not dose-dependent across the dose range evaluated (25-800 mg). An approximately dose-proportional increase in exposure (C max and area under the curve (AUC)) was observed, with no hypoglycemia. TAK-875 was well tolerated. Treatmentemergent adverse events (TEAEs) were not dose-dependent and were equivalent for the TAK-875 and placebo arms.TAK-875 is metabolized to its inactive metabolite M-I by oxidative cleavage of the ether linkage, to TAK-875-G by glucuronidation, and to TAK-875-Tau by conjugation with taurine. Glucuronidation appears to be the major metabolic pathway. TAK-875 appears to be eliminated primarily through hepatic metabolism, with negligible renal clearance. 8 Our primary objective was to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of oncedaily ascending oral doses of TAK-875 for 14 days in subjects with type 2 diabetes mellitus (T2DM). A secondary objective was exploratory assessment of its effect on short-term glycemic control. Results Demographics and dispositionA total of 59 subjects were enrolled in the study between January and July 2009; their data were included in the safety and PD analysis. The data for all 45 subjects who received TAK-875 were included in the PK analysis. Demographic and baseline characteristics were similar across treatment and placebo groups ( Table 1). Three subjects discontinued the study drug, one (from the TAK-875 25-mg group) because of an AE, one (from the TAK-875 400-mg group) through loss

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Context: Asoprisnil, a selective progesterone (P4) receptor (PR) modulator (SPRM) with mixed P4 agonist/antagonist activities, reduces uterine leiomyoma volume in a dose-dependent manner in the presence of follicular phase estrogen concentrations. The evidence from clinical studies suggests that asoprisnil may directly target the uterine leiomyomata. Objective and Methods:The present study evaluated the effects of asoprisnil on cell proliferation, the expression of apoptosis-related proteins, and apoptosis in cultured human uterine leiomyoma cells and matched normal myometrial cells. PR-A and PR-B expression in the two types of cells was comparatively evaluated. Cell proliferation, proliferating cell nuclear antigen (PCNA)-positive rate, and TUNEL-positive rate were assessed by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay, immunocytochemistry, and terminal deoxynucleotidyl transferase-mediated 2Ј-deoxyuridine 5Ј-triphosphate nick end labeling (TUNEL) assay, respectively. The expression of apoptosis-related proteins and PR was assessed by Western blot analysis. Results:Compared with untreated cultures, asoprisnil decreased the number of viable cultured cells, the PCNA-positive rate, and PCNA protein expression in cultured leiomyoma cells. Asoprisnil increased the TUNEL-positive rate, cleaved caspase-3, and cleaved poly(adenosine 5Ј-diphosphate-ribose) polymerase expression and decreased Bcl-2 protein expression in cultured leiomyoma cells. These effects were dose and time dependent. In cultured myometrial cells, however, asoprisnil did not affect cell proliferation and apoptosis. PR-B expression was elevated in cultured leiomyoma cells compared with cultured myometrial cells, whereas no differences in PR-A expression were noted between the two cell types. Conclusions:These results show that asoprisnil inhibits proliferation and induces apoptosis in cultured uterine leiomyoma cells in the absence of comparable effects on cultured normal myometrial cells, suggesting a cell type-specific effect.