Androgen receptor blocker (antagonist) 1 is an orally bioactive, intact androgen receptor (AR) antagonist (inhibitor) with IC50 of 59 nM. Androgen receptor blocker (antagonist) 1 may be utilized to prepare PROTAC AR degraders. 1 μM and 10 μM PROTAC AR degraders act on LNCaP cells, resulting in 24% and 47% AR protein degradation respectively.

Physicochemical Properties

Molecular Formula	C21H25CLN4O3
Molecular Weight	416.901203870773
Exact Mass	416.161
CAS #	1338812-36-4
PubChem CID	56643472
Appearance	White to off-white solid powder
LogP	3.1
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	5
Rotatable Bond Count	6
Heavy Atom Count	29
Complexity	646
Defined Atom Stereocenter Count	0
SMILES	ClC1=C(C#N)C=CC(=C1)OC1C(C)(C)C(C1(C)C)NC(C1C=NN(CCO)C=1)=O
InChi Key	HJJNHDLYWZTKGQ-UHFFFAOYSA-N
InChi Code	InChI=1S/C21H25ClN4O3/c1-20(2)18(25-17(28)14-11-24-26(12-14)7-8-27)21(3,4)19(20)29-15-6-5-13(10-23)16(22)9-15/h5-6,9,11-12,18-19,27H,7-8H2,1-4H3,(H,25,28)
Chemical Name	N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]-1-(2-hydroxyethyl)pyrazole-4-carboxamide
Synonyms	Androgen receptor antagonist 1; Androgen receptor antagonist 1
HS Tariff Code	2934.99.9001
Storage	Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

ln Vitro	Androgen receptor antagonist 1 (compound 26) had notable cytostatic effects on LNCaP and LNAR cells, while having no effect on DU145 cells [1].
ln Vivo	In an animal model of castration-resistant prostate cancer (CRPC), androgen receptor antagonist 1 (Compound 26; 100 mg/kg once daily for 5 weeks) showed good in vivo tumor growth reduction following oral administration [ 1].
Cell Assay	Cell proliferation assay[1] Cell Types: Prostate cancer (CaP) cells (LNCAP, LNAR and DU145) Tested Concentrations: 1 nM, 10 nM, 100 nM, 1 μM, 10 μM, 100 μM Incubation Duration: 7 days Experimental Results: Anti-proliferation Effects on LNCAP and LNAR cells.
Animal Protocol	Animal/Disease Models: Male athymic nude mouse LNCaP CRPC xenograft model [1] Doses: 100 mg/kg Route of Administration: Orally administered one time/day for 5 weeks. Experimental Results: It has a significant effect in inhibiting tumor growth. At the given dose (100 mg/kg one time/day), tumor growth (90% inhibition) and PSA levels (78%) were almost completely inhibited after 5 weeks, and no weight loss was detected in the animals during treatment.
References	[1]. Discovery of aryloxy tetramethylcyclobutanes as novel androgen receptor antagonists. J Med Chem. 2011 Nov 10;54(21):7693-704. [2]. Discovery of ARD-69 as a Highly Potent Proteolysis Targeting Chimera (PROTAC) Degrader of Androgen Receptor (AR) for the Treatment of Prostate Cancer. J Med Chem. 2019 Jan 24;62(2):941-964.

Solubility Data

Solubility (In Vitro)

DMSO : ~100 mg/mL (~239.87 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.00 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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.3987 mL	11.9933 mL	23.9866 mL
	5 mM	0.4797 mL	2.3987 mL	4.7973 mL
	10 mM	0.2399 mL	1.1993 mL	2.3987 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.