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Purity: =99%
Enclomiphene citrate, formerly known as ICI-46476, RMI-16289 and trans-Clomiphene, is a non-steroidal estrogen receptor antagonist that can be taken orally that is being developed as a treatment for secondary hypogonadism in overweight men who want to get their testicles back to normal. Unlike replacement, orally bioavailable enclomiphene citrate increases testosterone and maintains sperm counts in obese hypogonadal men.
| Targets |
ER/estrogen receptor
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|---|---|
| ln Vitro |
Enclomiphene citrate (0-100 μM, 6 h) suppresses gonadotrophin- and basal-stimulated small- and large-scale ovine luteal cell progesterone secretion in a dose-dependent manner[2].
Enclomiphene citrate (0-100 μg/mL, 24 h) dose-dependently suppresses the rates of blastocyst formation, degeneration, and fertilization in mouse oocytes[3]. Enclomiphene citrate (1 nM-10 μM, 6 h) dose-dependently reduces E2-induced inhibition of follicle stimulating hormone (FSH) secretion in primary sheep pituitary cells[4]. Enclomiphene (10⁻⁷ M) significantly increased basal progesterone secretion by small ovine luteal cells but not large luteal cells. In the presence of LH, it enhanced progesterone secretion in both cell types [2] Enclomiphene (10⁻⁵ M) did not affect development of mouse embryos from two-cell to blastocyst stage during in vitro fertilization [3] Enclomiphene (10⁻⁸–10⁻⁶ M) blocked estradiol-induced suppression of LH and FSH secretion in cultured ovine pituitary cells but showed no intrinsic agonistic activity [4] Enclomiphene (10⁻⁵ M) reduced estradiol-stimulated progesterone receptor expression in rat uterine tissue cultures [6] |
| ln Vivo |
In intact or castrated rats, clomiphene citrate (subcutaneous injection, 0.25 and 0.5 mg/animal, daily) inhibits spermatogenesis and lowers serum levels of testosterone and luteinizing hormone (LH)[5].
Enclomiphene citrate reduces serum cholesterol and body weight to sham levels when administered orally at a dose of 0.03–3 mg/kg per day for 90 days[6]. Enclomiphene (1 mg/kg) administered to pregnant mice did not alter blastocyst formation or implantation rates after in vivo fertilization [3] Enclomiphene (0.5 mg/kg/day for 10 days) increased testicular weight and serum testosterone in immature male rats [5] Enclomiphene (0.15 mg/kg/day for 4 days) elevated serum LH/FSH and antagonized estradiol-induced uterine weight gain in ovariectomized rats [6] |
| Cell Assay |
Progesterone secretion assay: Small and large ovine luteal cells were isolated via elutriation. Cells were treated with enclomiphene (10⁻⁷ M) with/without LH (10 ng/ml) for 3 hours. Progesterone in media was measured by radioimmunoassay [2]
Pituitary gonadotropin secretion assay: Ovine pituitary cells were cultured for 72 hours. Cells were exposed to enclomiphene (10⁻⁸–10⁻⁶ M) ± estradiol (10⁻⁹ M). LH and FSH in supernatants were quantified by RIA [4] Progesterone receptor expression: Uterine tissues from ovariectomized rats were cultured with enclomiphene (10⁻⁵ M) ± estradiol. Receptor levels were analyzed using immunoblotting [6] |
| Animal Protocol |
Mouse embryo development: Female mice received enclomiphene (1 mg/kg, route unspecified) on gestation days 1–2. Embryos were collected on day 3 for blastocyst assessment [3]
Immature rat testosterone study: Prepubertal male rats were injected subcutaneously with enclomiphene (0.5 mg/kg/day in saline) for 10 days. Testes and serum were collected for analysis [5] Ovariectomized rat model: Rats received subcutaneous enclomiphene (0.15 mg/kg/day in sesame oil) for 4 days ± estradiol benzoate (10 μg/kg). Uterine weight and serum hormones were measured [6] Animal/Disease Models: 21-day-old Charles River male rats [5] Doses: 0.25 and 0.5 mg/rat, one time/day for 24 days. Route of Administration: subcutaneous injection. Experimental Results: LH and testosterone levels in serum diminished. Animal/Disease Models: OVX (ovariectomy) rat model [6] Doses: 0.03, 1 and 3 mg/kg daily for 90 days. Method of Route of Administration: Oral administration Experimental Results: diminished body weight to sham levels and diminished serum cholesterol. demonstrated dose-dependent effects on the proximal tibia, with BMD and BMC approaching post-treatment sham levels. |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion
Based on early studies of clomiphene citrate labeled with 14C, this drug is readily absorbed orally in humans. Based on early studies of clomiphene citrate labeled with 14C, this drug is readily absorbed orally in humans and is primarily excreted via feces. The average urinary excretion rate is approximately 8%, and the fecal excretion rate is approximately 42%. Subcutaneous injection of clomiphene citrate labeled with 14C…distributed in the tissues of female newborn guinea pigs…estrogen-responsive tissues showed a high affinity for 14C. (14)C levels remained stable in the uterus…decreased in the ovaries and plasma…increased in the adrenal glands. /clomiphene citrate/ Approximately half of the ingested dose was excreted within five days; trace amounts of the drug remained in the feces for up to six weeks after administration. /Clomiphene Citrate/ Clomiphene is well absorbed after oral administration. The drug and its metabolites are primarily excreted in feces, with a small amount excreted in urine. The relatively long plasma half-life (approximately 5 to 7 days) is mainly due to plasma protein binding, enterohepatic circulation, and accumulation in adipose tissue. Long-lived active metabolites may also be produced. Metabolism/Metabolites Liver Incubation of the nonsteroidal anti-estrogenic clomiphene with rat liver microsomes resulted in the formation of 4-hydroxy, N-deethyl, and N-oxide metabolites, in stark contrast to previous similar experiments using rabbit microsomes, where only the first two metabolites were detected. No urinary excretion of the drug or its metabolites was detected after oral administration of clomiphene. 4-hydroxyclomiphene was the only detectable elimination product in the fecal extract. Liver Biological Half-Life 5-7 days |
| Toxicity/Toxicokinetics |
Toxicity Summary
Clomiphene possesses both estrogenic and anti-estrogenic properties, but its exact mechanism of action remains unclear. Clomiphene appears to stimulate the release of gonadotropins (follicle-stimulating hormone (FSH) and luteinizing hormone (LH)), thereby promoting follicular maturation, ovulation, and corpus luteum development and function, ultimately leading to pregnancy. The release of gonadotropins may be due to direct stimulation of the hypothalamic-pituitary axis, or it may be due to clomiphene competing with endogenous estrogens from the uterus, pituitary gland, or hypothalamus, thus reducing the inhibitory effect of estrogen on the hypothalamic-pituitary axis. Clomiphene has no significant progesterone, androgenic, or anti-androgenic effects and does not appear to interfere with the function of the pituitary-adrenal or pituitary-thyroid axis. Toxicity Data The acute oral LD50 of clomiphene is 1700 mg/kg in mice and 5750 mg/kg in rats. The toxic dose in humans is unknown. There are no reports of toxic reactions caused by acute overdose of clomiphene. During clomiphene treatment, if the dose exceeds the recommended dose, overdose symptoms may occur, including nausea, vomiting, vasomotor flushing, blurred vision, spotting or flashing lights in front of the eyes, scotomas, enlarged ovaries with pelvic or abdominal pain, etc. 6420009 Female TDLo Oral 73500 ug/kg/3 weeks Behavior: lucid; Behavior: toxic psychosis American Journal of Psychiatry, 154(1169), 1997 6420009 Male TDLo Oral 10 mg/kg/2 weeks-1 Behavior: hallucinations, perceptual distortion; Behavior: toxic psychosis; Behavior: irritability American Journal of Psychiatry, 154(1169), 1997 |
| References |
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| Additional Infomation |
According to state or federal labeling requirements, clomiphene citrate may be carcinogenic and developmentally toxic. Enclomiphene citrate is a highly bioavailable oral enclomiphene citrate salt. Enclomiphene is the trans isomer of clomiphene (a nonsteroidal triphenylene compound) and possesses tissue-selective estrogenic and anti-estrogenic activity. As a selective estrogen receptor modulator (SERM), enclomiphene binds to hypothalamic estrogen receptors, blocking the negative feedback of endogenous estrogen and stimulating the hypothalamus to release gonadotropin-releasing hormone (GnRH); the released GnRH then stimulates the anterior pituitary gland to release follicle-stimulating hormone (FSH) and luteinizing hormone (LH), leading to ovulation. Furthermore, the drug may bind to estrogen receptors on breast cancer cells, thereby inhibiting estrogen-stimulated proliferation in susceptible cell populations. The trans or (E)-isomer of clomiphene. See also: Clomiphene citrate (note moved here).
Enclomiphene is the trans isomer of clomiphene and, as a selective estrogen receptor antagonist in the pituitary/hypothalamus, increases the secretion of gonadotropins and testosterone in male patients with secondary hypogonadism[1]. Unlike clomiphene, enclomiphene lacks estrogenic activity in bone tissue and does not affect bone mineral density in rats[6]. |
| Molecular Formula |
C32H36CLNO8
|
|---|---|
| Molecular Weight |
598.089
|
| Exact Mass |
597.213
|
| Elemental Analysis |
C, 64.26; H, 6.07; Cl, 5.93; N, 2.34; O, 21.40
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| CAS # |
7599-79-3
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| Related CAS # |
Enclomiphene;15690-57-0;Clomiphene-d5 citrate;1217200-17-3;Enclomiphene hydrochloride;14158-65-7
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| PubChem CID |
6420009
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| Appearance |
White to off-white solid powder
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| Boiling Point |
509ºC at 760mmHg
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| Flash Point |
261.6ºC
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| LogP |
5.314
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
14
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| Heavy Atom Count |
42
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| Complexity |
708
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| Defined Atom Stereocenter Count |
0
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| SMILES |
Cl/C(/C1C=CC=CC=1)=C(\C1C=CC=CC=1)/C1C=CC(=CC=1)OCCN(CC)CC.OC(C(=O)O)(CC(=O)O)CC(=O)O
|
| InChi Key |
PYTMYKVIJXPNBD-BTKVJIOYSA-N
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| InChi Code |
InChI=1S/C26H28ClNO.C6H8O7/c1-3-28(4-2)19-20-29-24-17-15-22(16-18-24)25(21-11-7-5-8-12-21)26(27)23-13-9-6-10-14-23;7-3(8)1-6(13,5(11)12)2-4(9)10/h5-18H,3-4,19-20H2,1-2H3;13H,1-2H2,(H,7,8)(H,9,10)(H,11,12)/b26-25+
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| Chemical Name |
2-[4-[(E)-2-chloro-1,2-diphenylethenyl]phenoxy]-N,N-diethylethanamine;2-hydroxypropane-1,2,3-tricarboxylic acid
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| Synonyms |
ICI-46476; ICI 46476; ICI46476; Enclomiphene citrate; 7599-79-3; trans-Clomiphene citrate; Enclomid; Clomiphene b citrate; (E)-Clomiphene citrate; J303A6U9Y6; DTXSID80226887; RMI-16289; RMI 16289; RMI16289; (E)-Clomiphene citrate; Androxal; Enclomiphene citrate; Enclomid
|
| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: ~100 mg/mL (~167.2 mM)
Ethanol: ~2 mg/mL (~3.3 mM) |
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 0.83 mg/mL (1.39 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 8.3 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 0.83 mg/mL (1.39 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 8.3 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 0.83 mg/mL (1.39 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.6720 mL | 8.3599 mL | 16.7199 mL | |
| 5 mM | 0.3344 mL | 1.6720 mL | 3.3440 mL | |
| 10 mM | 0.1672 mL | 0.8360 mL | 1.6720 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT04887402 | Recruiting | Drug: Clomiphene Citrate | PCO Clomiphene Citrate |
Ain Shams Maternity Hospital | January 1, 2021 | |
| NCT05206448 | Recruiting | Drug: Letrozole Drug: Clomiphene Citrate |
PCOS Infertility |
Rachel Mejia | October 26, 2020 | Phase 4 |
| NCT03615547 | Not yet recruiting | Other: Placebo Drug: Clomiphene Citrate |
Azoospermia, Nonobstructive | Hospices Civils de Lyon | January 2023 | Phase 3 |
| NCT05106712 | Not yet recruiting | Drug: Vitamin D3 Drug: Clomiphene Citrate |
IVF Vitamin D Deficiency |
Umm Al-Qura University | November 1, 2021 | Not Applicable |
| NCT04944836 | Not yet recruiting | Procedure: Rotator Cuff Repair Drug: Clomiphene Citrate |
Rotator Cuff Tears | University of Utah | December 2022 | Phase 2 |
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