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Application of the goldilocks effect to the design of potent and selective inhibitors of phenylethanolamine N-methyltransferase: Balancing pKa and steric effects in the optimization of 3-methyl-1,2,3,4- tetrahydroisoquinoline inhibitors by beta-fluorination

3-Methyl-1,2,3,4-tetrahydroisoquinolines (3-methyl-THIQs) are potent inhibitors of phenylethanolamine N-methyltransferase (PNMT), but are not selective due to significant affinity for the alpha2-adrenoceptor. Fluorination of the methyl group lowers the pKa of the THIQ amine from 9.53 (CH3) to 7.88 (CH2F), 6.42 (CHF2), and 4.88 (CF3). This decrease in pKa results in a reduction in affinity for the alpha2-adrenoceptor. However, increased fluorination also results in a reduction in PNMT inhibitory potency, apparently due to steric and electrostatic factors. Biochemical evaluation of a series of 3-fluoromethyl-THIQs and 3-trifluoromethyl-THIQs showed that the former were highly potent inhibitors of PNMT, but were often nonselective due to significant affinity for the alpha2-adrenoceptor, while the latter were devoid of alpha2-adrenoceptor affinity, but also lost potency at PNMT. 3-Difluoromethyl-7-substituted-THIQs have the proper balance of both steric and pKa properties and thus have enhanced selectivity versus the corresponding 3-fluoromethyl-7-substituted-THIQs and enhanced PNMT inhibitory potency versus the corresponding 3-trifluoromethyl-7-substituted- THIQs. Using the “Goldilocks Effect” analogy, the 3-fluoromethyl-THIQs are too potent (too hot) at the alpha2-adrenoceptor and the 3-trifluoromethyl-THIQs are not potent enough (too cold) at PNMT, but the 3-difluoromethyl-THIQs are just right. They are both potent inhibitors of PNMT and highly selective due to low affinity for the alpha2- adrenoceptor. This seems to be the first successful use of the beta-fluorination of aliphatic amines to impart selectivity to a pharmacological agent while maintaining potency at the site of interest.

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Tetrahydroisoquinoline – Wikipedia,
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GLYCOLATE OXIDASE INHIBITORS FOR THE TREATMENT OF DISEASE

Described herein are compounds, methods of making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods of using such compounds to treat or prevent diseases or disorders associated with the enzyme glycolate oxidase (GO). Such diseases or disorders include, for example, disorders of glyoxylate metabolism, including primary hyperoxaluria, that are associated with production of excessive amounts of oxalate.

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Tetrahydroisoquinoline – Wikipedia,
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1-HYDROXY NAPHTHYRIDINE COMPOUNDS AS ANTI-HIV AGENTS

1-Hydroxy naphthyridine compounds (e.g., 1-hydroxy naphthyridin-2(1H)-one compounds of Formula I are inhibitors of HIV integrase and/or HIV RNase H and inhibitors of HIV replication: (I) wherein X and R1-R6 are as defined herein. The compounds are useful in the prophylaxis and treatment of infection by HIV and in the prophylaxis, delay in the onset, and treatment of AIDS. The compounds are employed against HIV infection and AIDS as compounds per se or in the form of pharmaceutically acceptable salts. The compounds and their salts can be employed as ingredients in pharmaceutical compositions, optionally in combination with other anti-HIV agents such as HIV antivirals, immunomodulators, antibiotics and vaccines.

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Redox condensation of o-halonitrobenzene with 1,2,3,4-tetrahydroisoquinoline: Involvement of an unexpected auto-catalyzed redox cascade

A practical synthesis of fused benzimidazoles 5 has been developed by simply heating o-halonitrobenzenes 1 with tetrahydroisoquinolines 2. In this transformation, 2 played multiple roles as a building block, base and a double hydride donor in a cascade of uncatalyzed aromatic substitution, reduction of the nitro group, oxidation of the alpha-methylene group and condensation.

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Tetrahydroisoquinoline – Wikipedia,
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4, 6-DISUBSTITUTED 2-AMINO-PYRIMIDINES AS HISTAMINE H4 RECEPTOR MODULATORS

The present invention relates to substituted heterocyclic compounds of Formula (I) or pharmaceutically acceptable salts or N-oxides or quaternary ammoniuna salts thereof wherein constituent members are provided herein with, as well as their compositions and methods of use, which are histamine H4 receptor inhibitors/antagonists useful in the treatment of histamine H4 receptor-associated conditions or diseases or disorders including, for example, inflammatory diseases or disorders, pruritus, and pain

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Tetrahydroisoquinoline – Wikipedia,
1,2,3,4-Tetrahydroisoquinoline | C9H11N – PubChem

Discovery of 7-Bromo-1,2,3,4-tetrahydroisoquinoline

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Substituted ring compound and its method and use thereof (by machine translation)

The present invention provides substituted ring compound and its method of use and use. The compounds of formula (I) compound shown by the formula (I) as shown in the stereo isomers, geometric isomers, tautomers, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or its prodrug. The invention also provides a pharmaceutical composition, said compound and said pharmaceutical composition can be of the organism within the sample protein kinase live, for protection, processing, treatment or alleviation of patient proliferative diseases. (by machine translation)

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Tetrahydroisoquinoline – Wikipedia,
1,2,3,4-Tetrahydroisoquinoline | C9H11N – PubChem

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Dehydrogenation of Nitrogen Heterocycles Using Graphene Oxide as a Versatile Metal-Free Catalyst under Air

Graphene oxide (GO) has been developed as an inexpensive, environmental friendly, metal-free carbocatalyst for the dehydrogenation of nitrogen heterocycles. Valuable compounds, such as quinoline, 3,4-dihydroisoquinoline, quinazoline, and indole derivatives, have been successfully used as substrates. The investigation of various oxygen-containing molecules with different conjugated systems indicated that both the oxygen-containing groups and large pi-conjugated system in GO sheets are essential for this reaction. (Figure presented.).

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Tetrahydroisoquinoline – Wikipedia,
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Biphenyl-2-carboxylic acid-tetrahydro-isoquinolin-6-yl amide derivatives, their preparation and their use as inhibitors of microsomal triglyceride transfer protein and/or apolipoprotein B (Apo B) secretion

Compounds of formula (I), STR1 wherin X is CH2, CO, CS or SO2 ; Y is selected from: a direct link, aliphatic hydrocarbylene radicals having up to 20 carbon atoms, which radical may be mono-substituted by hydroxy, (C1 -C10)alkoxy, (C1 -C10)acyl, (C1 -C10)acyloxy, or (C6 -C10)aryl, NH, and O, provided that if X is CH2,Y is a direct link; Z is selected from the following groups: (1) H, halo, cyano, (2) hydroxy, (C1 -C10)alkoxy, (C1 -C10)a1kylthio, (C1 -C10)acyl, thiophenylcaronyl (C1 -C10)alkoxycarbonyl, (3) (C1 -C10)aklkyammo, di(C1 -C10)alylamino, (C6 -C10)aryl(C1 -C10)alkylamino, provided that Y is not O or NH, (4) unsubstituted vinyl, (C6 -C10)aryl, (C3 -C8)cycloalkyl and fused benz derivatives thereof, (C7 -C10)polycycloalkyl, (C4 -C8)cycloalkenyl, (C7 -C10)polycycloalkenyl, (5) (C6 -C10)aryloxy, (C6 -C10)aryltio, (C6 -C10)aryl(C1 -C10)alkoxy, (C6 -C10)aryl(C1 -C10)alkylthio, (C3 -C8)cycloalkyloxy, (C4 -C8)cycloalkenyloxy, (6) heterocyclyl sclected from the group consisting of monocyclic radicals and fused polycycuic radicals, wherein said radicals contain a total of from 5 to 14 ring atoms, wherein said radicals contain a total of from 1 to 4 ring heteroatoms independently selocted from oxygen, nitrogen, and sulfur, and wherein the individual rings of said radicals may be independendy satated, partally unsaturated, or aromatic, provided that if X is CH2, Z is H or is selected from groups (4) and (6), wherein, when Z contains one or more rings, said rings may each independently bear 0 to 4 substituents independently selected from halo, hydroxy, cyano, nitro, oxo, thioxo, aminosulfonyl, phenyl phenoxy, phenylthio, halophenylthio, benzyl, benzyloxy, (C1 -C10)alkyl, (C1 -C10)alkoxy, (C1 -C10)alkoxycarbonyl, (C1 -C10)althyltio, (C1 -C10)altylamino, (C1 -C10)alkylaminocarbonyl, di(C1 -C10)alkylamino, di(C1 -C10)alkylaminocarbonyl, di(C1 -C10)alkyo(C1 -C10)alkoxy, (C1 -C3)perfluoroalkyl, (C1 -C3)perfluoroalkoxy, (C1 -C10)acyl, (C1 -C10)acyloxy, (C1 -C10)acyloxy(C1 -C10)alkyl, and pyrrolidinyl; and pharmaceutically acceptable salts thereof.

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Tetrahydroisoquinoline – Wikipedia,
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Lactam and oxazolidinone derived potent 5-hydroxytryptamine 6 receptor antagonists

Lactam and oxazolidinone derived potent 5-hydroxytryptamine 6 (5-HT 6) receptor antagonists have been disclosed. One potent member from the lactam series, racemic compound 14 (Ki of 2.6 nM in binding assay, IC50 of 15 nM in functional cAMP antagonism assay) was separated into corresponding enantiomers that displayed the effect of chirality on binding potency (Ki of 1.6 nM and 3000 nM, respectively). The potent enantiomer displayed an IC50 of 8 nM in cAMP antagonism assay, selectivity against a number of family members as well as brain permeability in rats after 6 h post oral administration.

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Catalyst-free cyclization of anthranils and cyclic amines: One-step synthesis of rutaecarpine

An efficient synthesis of a variety of quinazolinone derivatives via a direct cyclization reaction between commercially available anthranils and cyclic amines is described. The developed transformation proceeds with the merits of high step- and atom-efficiency, a broad substrate scope, and good to excellent yields, without additional catalysts, and offers a practical way for the preparation of rutaecarpine and its derivatives with structural diversity.

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Tetrahydroisoquinoline – Wikipedia,
1,2,3,4-Tetrahydroisoquinoline | C9H11N – PubChem