PF-00446687 is a potent, brain-penetrating, selective melanocortin 4 receptor (MC4R) agonist with EC50 of 12 ± 1 nM.

Physicochemical Properties

Molecular Formula	C28H36N2O2F2
Molecular Weight	470.59444
Exact Mass	470.274
CAS #	862281-92-3
PubChem CID	11328898
Appearance	White to off-white solid powder
LogP	4.656
Hydrogen Bond Donor Count	1
Hydrogen Bond Acceptor Count	5
Rotatable Bond Count	4
Heavy Atom Count	34
Complexity	708
Defined Atom Stereocenter Count	4
SMILES	C[C@@H]1CN(C[C@@H](C1(C2=CC=CC=C2)O)C)C(=O)[C@@H]3CN(C[C@H]3C4=C(C=C(C=C4)F)F)C(C)(C)C
InChi Key	WHPJOAUPIZDJNX-YTEQHECZSA-N
InChi Code	InChI=1S/C28H36F2N2O2/c1-18-14-31(15-19(2)28(18,34)20-9-7-6-8-10-20)26(33)24-17-32(27(3,4)5)16-23(24)22-12-11-21(29)13-25(22)30/h6-13,18-19,23-24,34H,14-17H2,1-5H3/t18-,19+,23-,24+,28?/m0/s1
Chemical Name	[(3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidin-3-yl]-[(3S,5R)-4-hydroxy-3,5-dimethyl-4-phenylpiperidin-1-yl]methanone
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	MC4 absorption is bound by PF-00446687, which has a Ki of 27±4 nM. PF-00446687 exhibits very low efficacy against MC1, MC3, and MC5 uptake, as seen by its respective EC50 values of 1.02±0.30 μM, 1.16±0.35 μM, and 1.98±0.20 μM. The CEREP Bioprint Broad Ligand Screening Panel assessed PF-00446687's extensive off-target profile and found that the compound had the strongest binding activity at muscarinic M2 uptake (Ki=730 nM), sodium channels (Ki=690 nM), and sigma receptors (Ki=330 nM) [1].
ln Vivo	Internally reaching the brain, Pf-446687 is stable and has great selectivity for MC4R. In prairie voles, but not in non-monogamous meadow voles, peripheral injection of the highly selective small molecule MC4R agonist Pf-446687 and the brain-penetrating MC3/4R receptor peptide agonist Melanotan II (MTII) can accelerate the establishment of dietary preferences. It is devoid of any [2].
References	[1]. Discovery of a selective small-molecule melanocortin-4 receptor agonist with efficacy in a pilot study of sexual dysfunction in humans. J Med Chem. 2010 Apr 22;53(8):3183-97. [2]. Melanocortin Receptor Agonists Facilitate Oxytocin-Dependent Partner Preference Formation in the Prairie Vole. Neuropsychopharmacology. 2015 Jul;40(8):1856-65.
Additional Infomation	PF-00446687 has been investigated for the treatment of Erectile Dysfunction.

Solubility Data

Solubility (In Vitro)

DMSO : ~62.5 mg/mL (~132.81 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.08 mg/mL (4.42 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 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL 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: ≥ 2.08 mg/mL (4.42 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. Solubility in Formulation 3: ≥ 2.08 mg/mL (4.42 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.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.1250 mL	10.6250 mL	21.2499 mL
	5 mM	0.4250 mL	2.1250 mL	4.2500 mL
	10 mM	0.2125 mL	1.0625 mL	2.1250 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.