Androgen receptor
Androgen receptor (Selective Androgen Receptor Modulator, SARM) [1]

LY2452473 is a selective androgen receptor modulator under development to treat hypogonadism-related illnesses. LY2452473 is cleared slowly (plasma terminal t1/2 of 51 h for the total radioactivity and 27 h for LY2452473) and absorbed quickly (time to reach maximum plasma concentration for both LY2452473 and total radioactivity is 2-3 h)[1].

P450 Reaction Phenotyping (Substrate Depletion): Incubations were performed to identify cytochrome P450 enzymes involved in the metabolism of LY2452473. Incubation mixtures contained potassium phosphate buffer, MgCl2, EDTA, and an NADPH-generating system. LY2452473 (1 μM for screening; 0.1 μM for optimized conditions) was incubated with a panel of recombinant human P450 enzymes (CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 2J2, 3A4, 3A5) or human liver microsomes (HLMs). Reactions were initiated by adding the NADPH-generating system and terminated by adding acetonitrile containing internal standards. Substrate depletion was monitored by LC-MS/MS. Intrinsic clearance (CLint) was calculated from the depletion rate constant. The relative contribution of each P450 was estimated by normalizing CLint values with reported hepatic P450 content. [1]
Chemical Inhibition in HLMs: LY2452473 (2 μM) was incubated in duplicate with HLMs in the presence of chemical inhibitors: sulfaphenazole (CYP2C9 inhibitor), modafinil (CYP2C19 inhibitor), quinidine (CYP2D6 inhibitor), and ketoconazole (CYP3A4/5 inhibitor) at various concentrations. Inhibition of substrate depletion was assessed after a 30-minute incubation. [1]

Human ADME Study Protocol: This was a single-dose study in six healthy male volunteers (ages 22-48). Each subject received a single oral dose of 15 mg LY2452473 (containing approximately 100 μCi of [14C]LY2452473). The dose was prepared by dissolving the compound in ethanol, then suspending with Ora-Plus and purified water. Subjects fasted from at least 10 hours before dosing until 4 hours after dosing. [1]

Absorption: Following a single oral dose of 15 mg, LY2452473 was rapidly absorbed, with the parent drug and total radioactivity reaching their maximum plasma concentration (tmax) in 2–3 hours. [1] Plasma exposure: The mean maximum plasma concentration (Cmax) of LY2452473 was 91.5 ng/mL, representing approximately 51% of the total radioactivity Cmax. The area under the concentration-time curve (AUC0-∞) of LY2452473 was 1330 ng·h/mL, representing approximately 17% of the total radioactivity exposure. [1] Elimination half-life: The mean terminal half-life (t1/2) of LY2452473 was 27 hours, and the mean terminal half-life of total radioactivity in plasma was 51 hours. [1]
Clearance and Volume of Distribution: The apparent systemic clearance (CL/F) was 11 L/h, and the terminal apparent volume of distribution (Vz/F) was 444 L. [1]
Excretion: The mean total recovery of radioactive material in excrement over 312 hours was 94.5% of the administered dose. Recovery in urine (47.9%) and feces (46.6%) was almost equal. Most (80%) of the dose was recovered within 120 hours of administration. Very little unmetabolized parent drug was detected in excrement (<2% of the dose), indicating that metabolic clearance is the primary elimination pathway. [1]
Metabolism: LY2452473 is extensively metabolized in the human body via multiple pathways. The major circulating substances in plasma included the parent drug (42% of total radioactive exposure based on AUC0-48), metabolite S5 (an acetamide, 21%), and metabolite S12 (a hydroxylated product on the cyclopentene ring, 35%). The largest excreted metabolite in feces was S10 (a diol formed via a cyclopentene-indole linker, approximately 14% of the dose). Other metabolic pathways included oxidation of the indole and pyridine rings, oxidation of isopropyl groups, N-oxidation, glucuronidation, and sulfation. No single metabolic pathway accounted for more than 30% of the dose in excretions. [1] Metabolic enzymes: An in vitro reaction phenotypic study in human liver microsomes (HLM) using recombinant P450 enzymes and chemical inhibitors showed that CYP3A4 was the major enzyme cleared from the liver of LY2452473 (estimated contribution of 68%). CYP2J2 was the second largest contributor (15%). CYP2C9, CYP2C19 and CYP2D6 have relatively minor effects. [1]

The article mentions that androgen use is usually limited by adverse reactions, including sleep apnea, acne, weight gain, hirsutism, voice changes, mood changes, hair loss, dyslipidemia, hematocrit, and abnormal liver function. [1]
Potential drug interactions: Based on the results of the morphological analysis, a clinical drug interaction study with CYP3A4 inhibitors (e.g., ketoconazole) is recommended. [1]

[1]. Disposition and metabolism of LY2452473, a selective androgen receptor modulator, in humans. Drug Metab Dispos. 2012 Dec;40(12):2354-64.

Ly2452473 is being investigated for adjuvant therapy in prostate cancer. Ly2452473 has also been used to treat erectile dysfunction. The selective androgen receptor modulator LY2452473 is an orally bioavailable selective androgen receptor modulator (SARM) with potential tissue-selective androgen/anti-androgen activity. After oral administration, LY2452473 acts as an agonist in specific tissues and organs, including skeletal muscle, bone, and the penis, binding to and activating androgen receptors (AR); while in the prostate, it acts as an antagonist, blocking AR activation and AR-mediated cell proliferation. This may help improve muscle mass and strength, promote bone formation, and improve erectile dysfunction without stimulating prostate growth. LY2452473 is a selective androgen receptor modulator (SARM) used to treat male hypogonadism-related disorders. It is considered to have the potential advantage of tissue selectivity, designed to produce beneficial effects on bone, muscle and erectile function (as an adjunct to PDE5 inhibitors) while minimizing steroid-related adverse reactions. [1]
LY2452473 has the chemical name is isopropyl N-[(2S)-7-cyano-4-(2-pyridinylmethyl)-2,3-dihydro-1H-cyclopentano[b]indol-2-yl]carbamate. [1]
The metabolite S10 exhibits interesting chemical properties, converting to the corresponding epoxide under acidic conditions and back to the diol under neutral conditions. [1]

C22H22N4O2

374.435684680939

374.174

C, 70.57; H, 5.92; N, 14.96; O, 8.55

1029692-15-6

1029692-15-6

24963749

White to off-white solid powder

3.762

1

4

5

28

615

1

O(C(C)C)C(N[C@H]1CC2C3C=C(C#N)C=CC=3N(CC3C=CC=CN=3)C=2C1)=O

IHIWYQYVBNODSV-KRWDZBQOSA-N

InChI=1S/C22H22N4O2/c1-14(2)28-22(27)25-17-10-19-18-9-15(12-23)6-7-20(18)26(21(19)11-17)13-16-5-3-4-8-24-16/h3-9,14,17H,10-11,13H2,1-2H3,(H,25,27)/t17-/m0/s1

propan-2-yl N-[(2S)-7-cyano-4-(pyridin-2-ylmethyl)-2,3-dihydro-1H-cyclopenta[b]indol-2-yl]carbamate

LY2452473; LY 2452473; LY-2452473

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: ~62.5 mg/mL (~166.9 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (5.55 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 20.8 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.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (5.55 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)