HTL14242 (HTL-14242; HTL0014242; HTL-0014242) is a novel, oral and potent mGlu5 NAM (negative allosteric modulator) (pKi and pIC50 value = 9.3 and 9.2) with the potential to be used for Parkinson's disease. Metabotropic glutamate receptors (mGluRs) constitute the class C of G-protein coupled receptors (GPCRs) and play a key role in glutamatergic signaling. The inhibition of mGluR5, which is mostly expressed in the striatum, hippocampus, amygdala, and frontal cortex, is therefore considered as a potential therapeutic intervention in a number of psychiatry indications, including fragile X syndrome, anxiety, and depression.

Physicochemical Properties

Molecular Formula	C16H8CLFN4
Molecular Weight	310.712924957275
Exact Mass	310.042
CAS #	1644645-32-8
PubChem CID	86763358
Appearance	White to yellow solid powder
LogP	2.9
Hydrogen Bond Donor Count	0
Hydrogen Bond Acceptor Count	5
Rotatable Bond Count	2
Heavy Atom Count	22
Complexity	426
Defined Atom Stereocenter Count	0
SMILES	ClC1C=C(C#N)C=C(C=1)C1C=C(C2C=CC(=CN=2)F)N=CN=1
InChi Key	FQAXDSVNYVVQSE-UHFFFAOYSA-N
InChi Code	InChI=1S/C16H8ClFN4/c17-12-4-10(7-19)3-11(5-12)15-6-16(22-9-21-15)14-2-1-13(18)8-20-14/h1-6,8-9H
Chemical Name	3-chloro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzonitrile
Synonyms	HTL 14242 HTL-14242 HTL0014242HTL-0014242 HTL14242
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

Targets	mGlu5
ln Vitro	In vitro cytotoxicity studies on HepG2 cells show that HTL14242 is stable in rat plasma, inactive at the hERG ion-channel, and has a clean profile with a TC50 of >90 μM[1].
ln Vivo	With an estimated ED50 of 0.3 mg/kg, HTL14242 (oral administration; 1, 3, or 10 mg/kg; sacrificed 1 h postdose) exhibits an excellent, dose-dependent occupancy of mGlu5 receptors from an oral dose[1]. (oral dosing; 1 mg/ml) shows an oral PK Profile in dogs; the t1/2, AUCinf, and F% are, respectively, 6.5 hours, 3946 ng/h/mL, and 80%[1].
Animal Protocol	Animal/Disease Models: Dog ( PK study)[1] Doses: 3, 10 and 30 mg/kg Route of Administration: Oral administration; single dose Experimental Results: Had a good PK characteristics in dogs.
References	[1]. Structure-based Discovery and Development of Metabotropic Glutamate Receptor 5 Negative Allosteric Modulators. Adv Pharmacol. 2020;88:35-58. [2]. Fragment and Structure-Based Drug Discovery for a Class C GPCR: Discovery of the mGlu5 Negative Allosteric Modulator HTL14242 (3-Chloro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzonitrile). J Med Chem. 2015 Aug 27;58(16):66.

Solubility Data

Solubility (In Vitro)

DMSO : ~12.5 mg/mL (~40.23 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 1.25 mg/mL (4.02 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 12.5 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	3.2184 mL	16.0922 mL	32.1844 mL
	5 mM	0.6437 mL	3.2184 mL	6.4369 mL
	10 mM	0.3218 mL	1.6092 mL	3.2184 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.