RTI-7470-44

RTI-7470-44
Clinical data
Drug class	TAAR1 antagonist
Identifiers
	IUPAC name 2-[6-(4-chlorophenyl)-3-cyano-4-(trifluoromethyl)pyridin-2-yl]sulfanyl-N-pyrimidin-2-ylacetamide;
CAS Number	825658-63-7;
PubChem CID	2225078;
ChemSpider	1663640;
Chemical and physical data
Formula	C19H11ClF3N5OS
Molar mass	449.84 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES C1=CN=C(N=C1)NC(=O)CSC2=C(C(=CC(=N2)C3=CC=C(C=C3)Cl)C(F)(F)F)C#N;
	InChI InChI=1S/C19H11ClF3N5OS/c20-12-4-2-11(3-5-12)15-8-14(19(21,22)23)13(9-24)17(27-15)30-10-16(29)28-18-25-6-1-7-26-18/h1-8H,10H2,(H,25,26,28,29); Key:WHNQNKYKDSLDKM-UHFFFAOYSA-N;

RTI-7470-44 is a potent and selective antagonist of the human trace amine-associated receptor 1 (TAAR1) which is used in scientific research.^[1]^[2]^[3]^[4] It was discovered in 2022 and is the first potent antagonist of the human TAAR1 to be identified, following the potent mouse TAAR1 inverse agonist EPPTB in 2009.^[3]^[4]^[5]

The affinity (K_i) of RTI-7470-44 for the human TAAR1 is 0.3 nM and its inhibitory potency (IC₅₀Tooltip half-maximal inhibitory concentration) at the receptor is 8.4 nM in vitro.^[2]^[4] It is about 90-fold less potent at the rat TAAR1 (IC₅₀ = 748 nM) and 140-fold less potent at the mouse TAAR1 (IC₅₀ = 1,190 nM) compared to the human TAAR1.^[2]^[4] Surprisingly, RTI-7470-44 was found to be a competitive antagonist of the human and mouse TAAR1 but a non-competitive antagonist of the rat TAAR1.^[4]

The compound has favorable in vivo drug-like properties, including good blood–brain barrier permeability, moderate metabolic stability, and a favorable preliminary profile of off-target activity (≥1–10 μM at 42 other targets).^[1]^[3]^[4] It is far more potent (893-fold) as an antagonist of the human TAAR1 than the earlier TAAR1 inverse agonist EPPTB in vitro, which has dramatically lower potency (165–272-fold) at the human TAAR1 and rat TAAR1 compared to the mouse TAAR1.^[4]

RTI-7470-44 has been found to increase the spontaneous firing rate of dopaminergic neurons in mouse ventral tegmental area (VTA) slices ex vivo and to block the effects of the TAAR1 agonist RO5166017 in this system.^[1]^[3]^[4]

RTI-7470-44 was first described in the scientific literature in 2022.^[2]^[4] It was identified via high throughput screening followed by structure–activity optimization.^[1]^[4]

References

^ ^a ^b ^c ^d Scarano N, Espinoza S, Brullo C, Cichero E (July 2024). "Computational Methods for the Discovery and Optimization of TAAR1 and TAAR5 Ligands". Int J Mol Sci. 25 (15): 8226. doi:10.3390/ijms25158226. PMC 11312273. PMID 39125796. On the other hand, HTS approaches [100] followed by structure-activity optimization allowed for the discovery of the hTAAR1 antagonist RTI-7470-44, endowed with a species-specificity preference over mTAAR1 (Figure 11A) [99]. RTI-7470-44 displayed good blood–brain barrier permeability, moderate metabolic stability, and a favorable preliminary off-target profile. In addition, RTI-7470-44 increased the spontaneous firing rate of mouse ventral tegmental area (VTA) dopaminergic neurons and blocked the effects of the known TAAR1 agonist RO5166017. [...] Figure 11. (A) Chemical structures of the available hTAAR1 agonists: EPPTB [98], RTI-7470-44 [99], and 4c [33], [...] RTI-7470-44: hTAAR1 IC50 = 0.0084 μM, mTAAR1 IC50 = 1.190 μM.
^ ^a ^b ^c ^d Zilberg G, Parpounas AK, Warren AL, Yang S, Wacker D (January 2024). "Molecular basis of human trace amine-associated receptor 1 activation". Nat Commun. 15 (1): 108. Bibcode:2024NatCo..15..108Z. doi:10.1038/s41467-023-44601-4. PMC 10762035. PMID 38168118. Studies have shown that there are considerable functional and pharmacological differences between hTA1 and TA1 in rats (rTA1) or mice (mTA1)12, with key implications for translating findings from preclinical models into human therapies. For instance, TYR has been reported to be ~30 times more potent at rTA1 than hTA1, and the antagonist EPPTB was shown to have an affinity of ~1 nM at mTA1 but does not appear to bind hTA132. Inversely, the recently reported TA1 antagonist RTI-7470-44 has an IC50 of about 8 nM at hTA1 but shows ~90-fold and ~140-fold reduced potencies at rTA1 and mTA1, respectively33.
^ ^a ^b ^c ^d Liu J, Wu R, Li JX (January 2024). "TAAR1 as an emerging target for the treatment of psychiatric disorders". Pharmacol Ther. 253: 108580. doi:10.1016/j.pharmthera.2023.108580. PMID 38142862. Similar to EPPTB, RTI-7470-44 could increase the spontaneous firing rate of dopaminergic neurons in mice VTA slices and prevent the effects of TAAR1 agonist RO5166017 (Decker et [...] Furthermore, RTI-7470-44 has appropriate properties for in vivo use, including favorable preliminary off-target profile, moderate metabolic stability, and good blood-brain barrier permeability [...] However, currently there is no behavioral study that investigated the effects of RTI-7470-44. Compared to the limited literature on TAAR1 antagonists, many TAAR1 agonists have been [...]
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j Decker AM, Brackeen MF, Mohammadkhani A, Kormos CM, Hesk D, Borgland SL, Blough BE (April 2022). "Identification of a Potent Human Trace Amine-Associated Receptor 1 Antagonist". ACS Chem Neurosci. 13 (7): 1082–1095. doi:10.1021/acschemneuro.2c00086. PMC 9730857. PMID 35325532.
^ Bradaia A, Trube G, Stalder H, Norcross RD, Ozmen L, Wettstein JG, Pinard A, Buchy D, Gassmann M, Hoener MC, Bettler B (November 2009). "The selective antagonist EPPTB reveals TAAR1-mediated regulatory mechanisms in dopaminergic neurons of the mesolimbic system". Proc Natl Acad Sci U S A. 106 (47): 20081–20086. Bibcode:2009PNAS..10620081B. doi:10.1073/pnas.0906522106. PMC 2785295. PMID 19892733.

[ScaranoEspinozaBrullo2024-1] Scarano N, Espinoza S, Brullo C, Cichero E (July 2024). "Computational Methods for the Discovery and Optimization of TAAR1 and TAAR5 Ligands". Int J Mol Sci. 25 (15): 8226. doi:10.3390/ijms25158226. PMC 11312273. PMID 39125796. On the other hand, HTS approaches [100] followed by structure-activity optimization allowed for the discovery of the hTAAR1 antagonist RTI-7470-44, endowed with a species-specificity preference over mTAAR1 (Figure 11A) [99]. RTI-7470-44 displayed good blood–brain barrier permeability, moderate metabolic stability, and a favorable preliminary off-target profile. In addition, RTI-7470-44 increased the spontaneous firing rate of mouse ventral tegmental area (VTA) dopaminergic neurons and blocked the effects of the known TAAR1 agonist RO5166017. [...] Figure 11. (A) Chemical structures of the available hTAAR1 agonists: EPPTB [98], RTI-7470-44 [99], and 4c [33], [...] RTI-7470-44: hTAAR1 IC50 = 0.0084 μM, mTAAR1 IC50 = 1.190 μM.

[ZilbergParpounasWarren2024-2] Zilberg G, Parpounas AK, Warren AL, Yang S, Wacker D (January 2024). "Molecular basis of human trace amine-associated receptor 1 activation". Nat Commun. 15 (1): 108. Bibcode:2024NatCo..15..108Z. doi:10.1038/s41467-023-44601-4. PMC 10762035. PMID 38168118. Studies have shown that there are considerable functional and pharmacological differences between hTA1 and TA1 in rats (rTA1) or mice (mTA1)12, with key implications for translating findings from preclinical models into human therapies. For instance, TYR has been reported to be ~30 times more potent at rTA1 than hTA1, and the antagonist EPPTB was shown to have an affinity of ~1 nM at mTA1 but does not appear to bind hTA132. Inversely, the recently reported TA1 antagonist RTI-7470-44 has an IC50 of about 8 nM at hTA1 but shows ~90-fold and ~140-fold reduced potencies at rTA1 and mTA1, respectively33.

[LiuWuLi2024-3] Liu J, Wu R, Li JX (January 2024). "TAAR1 as an emerging target for the treatment of psychiatric disorders". Pharmacol Ther. 253: 108580. doi:10.1016/j.pharmthera.2023.108580. PMID 38142862. Similar to EPPTB, RTI-7470-44 could increase the spontaneous firing rate of dopaminergic neurons in mice VTA slices and prevent the effects of TAAR1 agonist RO5166017 (Decker et [...] Furthermore, RTI-7470-44 has appropriate properties for in vivo use, including favorable preliminary off-target profile, moderate metabolic stability, and good blood-brain barrier permeability [...] However, currently there is no behavioral study that investigated the effects of RTI-7470-44. Compared to the limited literature on TAAR1 antagonists, many TAAR1 agonists have been [...]

[DeckerBrackeenMohammadkhani2022-4] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j Decker AM, Brackeen MF, Mohammadkhani A, Kormos CM, Hesk D, Borgland SL, Blough BE (April 2022). "Identification of a Potent Human Trace Amine-Associated Receptor 1 Antagonist". ACS Chem Neurosci. 13 (7): 1082–1095. doi:10.1021/acschemneuro.2c00086. PMC 9730857. PMID 35325532.

[BradaiaTrubeStalder2009-5] Bradaia A, Trube G, Stalder H, Norcross RD, Ozmen L, Wettstein JG, Pinard A, Buchy D, Gassmann M, Hoener MC, Bettler B (November 2009). "The selective antagonist EPPTB reveals TAAR1-mediated regulatory mechanisms in dopaminergic neurons of the mesolimbic system". Proc Natl Acad Sci U S A. 106 (47): 20081–20086. Bibcode:2009PNAS..10620081B. doi:10.1073/pnas.0906522106. PMC 2785295. PMID 19892733.

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