Delving into the Latest Updates on Asoprisnil Ecamate with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Asoprisnil

+ [1]

Target

PR

Mechanism

PR modulators(Progesterone receptor modulators)

Therapeutic Areas

NeoplasmsUrogenital DiseasesOther Diseases

Active Indication-

Inactive Indication

AmenorrheaEndometriosisLeiomyoma+ [4]

Originator Organization

Jenapharm GmbH & Co. KG

Active Organization-

Inactive Organization

Abbott Laboratories

Jenapharm GmbH & Co. KG

Takeda Pharmaceutical Co., Ltd.

Drug Highest PhaseDiscontinuedPhase 3

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC31H40N2O5

InChIKeyXMCOWVOJIVSMEO-RCCUTSCYSA-N

CAS Registry222732-94-7

Progesterone (P4) is a vital female sex hormone involved in various physiological processes, including the maintenance of the endometrium, mammary gland development, and bone health. Beyond its reproductive roles, P4 is implicated in the pathogenesis of hormone-dependent conditions like uterine fibroids, the most common benign tumors in women, which can severely affect quality of life and fertility. Traditionally, estrogen was considered the primary driver of fibroid growth, but recent research highlights the significant role of P4 in fibroid growth. P4 interacts with progesterone receptors (PRs) and non-genomic membrane receptors (mPRs and PGRMCs) to activate signaling pathways that enhance tumor growth and survival. P4 promotes vascular changes that improve the blood supply to fibroids and modifies the extracellular matrix, a key component of fibroid structure. This understanding has led to the investigation of selective progesterone receptor modulators (SPRMs) as potential therapies for fibroids. Clinical trials have demonstrated the effectiveness of SPRMs like mifepristone, asoprisnil, and ulipristal acetate in reducing fibroid size and symptoms, though concerns about safety, particularly with long-term use, remain. Newer SPRMs, such as vilaprisan, show promise, but further research is necessary to assess the long-term safety and effectiveness. This review discusses the mechanisms by which progesterone contributes to fibroid growth and examines clinical effectiveness of SPRMs as potential treatments for uterine fibroids.

01 Jan 2023·Frontiers in endocrinology

Next step in the development of mesoprogestins: the preclinical profile of EC313.

Article

Author: Krupa, A ; Mnich, E ; Błaszczak-Świątkiewicz, K ; Oettel, M ; Shaked, Z ; Nair, H ; Elger, W ; Wierzbicki, M ; Sieroszewski, P

IntroductionThe pharmacological target for progesterone, different progestins, and Selective Progesterone Receptor Modulators (SPRMs) is the nuclear progesterone receptor (PR). EC313 is a new member of a subgroup of SPRMs, mesoprogestins, which combine especially PR- agonistic and PR-antagonistic activities in one molecule.MethodsThe suitable in vivo-model for the differentiation of SPRMs from the subgroup of mesoprogestins is the estrogen-primed juvenile rabbit endometrium assay (McPhail Assay). Remarkably, in contrast to other well-known SPRMs with no agonistic effects in this test, EC313 shows clear partial PR-agonistic effects that are higher than that of the well-known mesoprogestin Asoprisnil which already demonstrated remarkable clinical effectiveness for the treatment of uterine fibroids and endometriosis. The findings from the guinea pig studies presented here can be the impetus for further preclinical development of EC313. This model shows the same features for the termination of pregnancy by antiprogestins such as Mifepristone and Ulipristal acetate (UPA) in humans. Moreover, it is possible to distinguish between progestational and anti-progestational activities in the same experiment.ResultsThe EC313 treatment reveals PR dominance in the genital tract and inhibits unopposed estrogenic effects. In very high doses (30.0 mg/animal/day subcutaneously (s.c.)) given twice on pregnancy days 43 and 44, no premature labor was induced (in contrast to UPA, dosed at 10.0 and 30. mg/animal/day s.c.). The anti-ovulatory activity of EC313 exceeds that of Ulipristal acetate or Mifepristone. EC313 binds to the steroid receptors in vitro with a similar affinity as the natural ligand progesterone. At the glucocorticoid receptor (GR) EC313 acts as a weak inhibitor. Minor activities at the human androgen receptor (AR) and mineralocorticoid receptor (MR) are considered negligible. No binding to the estradiol receptor was detected. In contrast to some in vitro-receptor findings, estrogenic, anti-estrogenic, androgenic, anti-androgenic, glucocorticoid, and anti-glucocorticoid actions were absent in vivo. The tissue selectivity of EC313 was demonstrated previously by reducing the growth and proliferation of uterine fibroids in animal models (lowest effective dosage 0.1 mg/kg/day s.c.).. As shown in this article, the anti-fibroid activity of EC313 was confirmed with a 10 times lower dosage (0.01 mg/kg/day s.c.). It was also shown that EC313 reduces the growth of endometriotic lesions in a human xenograft immune-deficient (NOD-SCID) mice model with a comparatively very low dosage range. In the aforementioned EC313 activity model, UPA was tested as the reference compound, the clinical effectiveness of which has already been demonstrated.DiscussionFor an explanation of these findings, the possibility is discussed that the mixed agonistic/antagonistic feature of EC313 is tissue target-specific based on its super-additive synergism characteristic for active bifunctional agents. In conclusion, the specific pharmacodynamic profile of this compound opens the possibility for the development of a drug with a distinct pharmaco-endocrinological profile against uterine fibroids, endometriosis, and other PR-dependent gynecological diseases.

01 Oct 2020·Endocrine ReviewsQ1 · MEDICINE

Selective Progesterone Receptor Modulators—Mechanisms and Therapeutic Utility

Q1 · MEDICINE

Review

Author: Afrin, Sadia ; Segars, James ; Jones, Sara Isabel ; Islam, Md Soriful

AbstractSelective progesterone receptor modulators (SPRMs) are a new class of compounds developed to target the progesterone receptor (PR) with a mix of agonist and antagonist properties. These compounds have been introduced for the treatment of several gynecological conditions based on the critical role of progesterone in reproduction and reproductive tissues. In patients with uterine fibroids, mifepristone and ulipristal acetate have consistently demonstrated efficacy, and vilaprisan is currently under investigation, while studies of asoprisnil and telapristone were halted for safety concerns. Mifepristone demonstrated utility for the management of endometriosis, while data are limited regarding the efficacy of asoprisnil, ulipristal acetate, telapristone, and vilaprisan for this condition. Currently, none of the SPRMs have shown therapeutic success in treating endometrial cancer. Multiple SPRMs have been assessed for efficacy in treating PR-positive recurrent breast cancer, with in vivo studies suggesting a benefit of mifepristone, and multiple in vitro models suggesting the efficacy of ulipristal acetate and telapristone. Mifepristone, ulipristal acetate, vilaprisan, and asoprisnil effectively treated heavy menstrual bleeding (HBM) in patients with uterine fibroids, but limited data exist regarding the efficacy of SPRMs for HMB outside this context. A notable class effect of SPRMs are benign, PR modulator-associated endometrial changes (PAECs) due to the actions of the compounds on the endometrium. Both mifepristone and ulipristal acetate are effective for emergency contraception, and mifepristone was approved by the US Food and Drug Administration (FDA) in 2012 for the treatment of Cushing’s syndrome due to its additional antiglucocorticoid effect. Based on current evidence, SPRMs show considerable promise for treatment of several gynecologic conditions.

100 Deals associated with Asoprisnil Ecamate

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External Link

KEGG	Wiki	ATC	Drug Bank
-	Asoprisnil Ecamate	-	-

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Menorrhagia	Phase 3	-	Abbott Laboratories	01 Jul 2002
Metrorrhagia	Phase 3	-	Abbott Laboratories	01 Jul 2002
Endometriosis	Phase 3	-	Takeda Pharmaceutical Co., Ltd.	-
Endometriosis	Phase 3	-	Jenapharm GmbH & Co. KG	-
Endometriosis	Phase 3	-	Takeda Pharmaceutical Co., Ltd.	-
Endometriosis	Phase 3	-	Jenapharm GmbH & Co. KG	-
Leiomyoma	Phase 3	-	Jenapharm GmbH & Co. KG	-
Leiomyoma	Phase 3	-	Takeda Pharmaceutical Co., Ltd.	-
Menopausal symptoms	Phase 3	-	Jenapharm GmbH & Co. KG	-
Menopausal symptoms	Phase 3	-	Takeda Pharmaceutical Co., Ltd.	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT00156195 (Pubmed \| Hum Reprod Open) Manual	Phase 3	Menorrhagia \| Uterine Fibroids	436	asoprisnil (10 mg)	(ukrjsdtcpo) = xxoqbjeurf cidthnzhxr (zyadsevdlh )	Negative	04 Nov 2019
				asoprisnil (25 mg)	(ukrjsdtcpo) = pofyoxrpaz cidthnzhxr (zyadsevdlh )