Inhibitors of phenylethanolamine N-methyltransferase devoid of α2-adrenoceptor affinity

Grunewald, Gary L.; Lü, Jian; Criscione, Kevin R.; Okoro, Cosmas O.

doi:10.1016/j.bmcl.2005.08.033

Cited by 33 publications

(15 citation statements)

References 27 publications

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“…23,24 The 3-difluoromethyl-7-substituted-THIQs were found to have PNMT inhibitory potencies that were quite similar to the corresponding 3-fluoromethyl-7-substituted-THIQs. This is especially evident for the most potent 3-fluoromethyl-7-substituted-THIQs (11a-17a), which have hPNMT K i values of less than 300 nM.…”

Section: Resultsmentioning

confidence: 99%

“…Docking studies with 3-trifluoromethyl-THIQs showed that the trifluoromethyl group did not fit into the lipophilic channel due to negative steric interactions. 24 We hypothesized that THIQs having a 3-substituent that (1) sufficiently lowers the pK a of the THIQ amine to diminish affinity for the α 2 -adrenoceptor, and (2) is small enough to maintain potency at PNMT would be an ideal inhibitor. We reasoned that 3-difluoromethyl-THIQs could meet these criteria because (1) the pK a of the THIQ amine is reduced below 6.5, and (2) docking studies indicated that the 3-difluoromethyl group would be able to fit into the lipophilic channel.…”

Section: Introductionmentioning

confidence: 99%

“…This has been attributed to the increased steric bulk of the trifluoromethyl group. 23,24 Analysis of the crystal structure of human PNMT (hPNMT) co-crystallized with inhibitors [25][26][27] and substrates, 28 coupled with site directed mutagenesis studies, 27 has helped to identify the key amino acids at the hPNMT active site, some of which are shown in Figure 2. The aromatic rings of substrates or THIQ-type inhibitors are positioned between the side chains of Phe182 and Asn39.…”

Section: Introductionmentioning

confidence: 99%

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Application of the Goldilocks Effect to the Design of Potent and Selective Inhibitors of Phenylethanolamine N-Methyltransferase: Balancing pK_a and Steric Effects in the Optimization of 3-Methyl-1,2,3,4-tetrahydroisoquinoline Inhibitors by β-Fluorination

et al. 2006

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Abstract3-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 α 2 -adrenoceptor. Fluorination of the methyl group lowers the pK a of the THIQ amine from 9.53 (CH 3 ) to 7.88 (CH 2 F), 6.42 (CHF 2 ), and 4.88 (CF 3 ). This decrease in pK a results in a reduction in affinity for the α 2 -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 non-selective due to significant affinity for the α 2 -adrenoceptor, while the latter were devoid of α 2 -adrenoceptor affinity, but also lost potency at PNMT. 3-Difluoromethyl-7-substituted-THIQs have the proper balance of both steric and pK a 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-fluoromethylTHIQs are too potent (too hot) at the α 2 -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 α 2 -adrenoceptor. This seems to be the first successful use of the β-fluorination of aliphatic amines to impart selectivity to a pharmacological agent while maintaining potency at the site of interest.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Application of the Goldilocks Effect to the Design of Potent and Selective Inhibitors of Phenylethanolamine N-Methyltransferase: Balancing pK_a and Steric Effects in the Optimization of 3-Methyl-1,2,3,4-tetrahydroisoquinoline Inhibitors by β-Fluorination

et al. 2006

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“…This was not unexpected because previous studies have shown that the replacement of the 3-methyl group of 11 with a trifluoromethyl group results in a 190-fold reduction in hPNMT inhibitory potency for 65 (Table 3). 26 In these studies, we attributed the reduction in potency of 3-trifluoromethyl-THIQs versus 3-methyl-THIQs to the increased steric bulk of the trifluoromethyl group, specifically from unfavorable interactions with Tyr222. 24,26 Similarly, docking studies (not shown) indicate that the decrease in hPNMT inhibitory potency of the 6-trifluoromethyl-THTPs is most likely due these same factors.…”

Section: -Substituted-thtps Versus 3-substituted-thiqs-mentioning

confidence: 99%

Synthesis of 4,5,6,7-tetrahydrothieno[3,2-c]pyridines and comparison with their isosteric 1,2,3,4-tetrahydroisoquinolines as inhibitors of phenylethanolamine N-methyltransferase

Grunewald

Seim

Bhat

et al. 2008

Bioorganic & Medicinal Chemistry

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A series of substituted 4,5,6,7-tetrahydrothieno[3,2-c]pyridines (THTPs) was synthesized and evaluated for their human phenylethanolamine N-methyltransferase (hPNMT) inhibitory potency and affinity for the α 2 -adrenoceptor. The THTP nucleus was suggested as an isosteric replacement for the 1,2,3,4-tetrahydroisoquinoline (THIQ) ring system on the basis that 3-thienylmethylamine (18) was more potent as an inhibitor of hPNMT and more selective towards the α 2 -adrenoceptor than benzylamine (15). Although the isosterism was confirmed, with similar influence of functional groups and chirality in both systems on hPNMT inhibitory potency and selectivity, the THTP compounds proved, in general, to be less potent as inhibitors of hPNMT than their THIQ counterparts, with the drop in potency being primarily attributed to the electronic properties of the thiophene ring. A hypothesis for the reduced hPNMT inhibitory potency of these compounds has been formed on the basis of molecular modeling and docking studies using the X-ray crystal structures of hPNMT co-crystallized with THIQ-type inhibitors and S-adenosyl-L-homocysteine as a template.

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“…However, the majority of these compounds are based on 1,2,3,4-tetrahydroisoquinoline and its analogues. [6][7][8][9][10] We reported three potential and novel inhibitors of hPNMT (YPN010, YPN016 and YPN017) using 3D pharmacophore-based in silico screening, biophysical screening and enzymatic activity assay. 11 These YPN inhibitors and known inhibitors of hPNMT such as THIQ and 2-aminoindan are shown in Figure 1.…”

Section: Introductionmentioning

confidence: 99%

Mutagenic Analysis of hPNMT Confirms the Importance of Lys57 and the Inhibitor Binding Site

Jeong¹,

Kang²,

Lee³

et al. 2011

Bulletin of the Korean Chemical Society

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In previous report, with the aid of receptor-oriented pharmacophore-based in silico screening, we characterized three novel hPNMT inhibitors (YPN010, YPN016, and YPN017) and proposed that the hydrogen bonding interaction between inhibitors and side chain of Lys57 is very important to inhibitory activity of hPNMT. To confirm the importance of Lys57, mutant with substitution of Lys57 with Ala was cloned and binding study was performed for a K57A mutant of hPNMT using STD-NMR and fluorescence experiments. The binding constants for three novel inhibitors with mutant hPNMT were dramatically decreased compared to those with wild-type protein. K57A mutant-induced conversion of noradrenaline to adrenaline was suppressed about 95 % compared to wild-type hPNMT. Mutagenic analysis using a K57A mutant confirmed the importance of the Lys57 residue in binding of the inhibitor candidate to hPNMT as well as enzymatic activity of hPNMT, implying that these results are consistent with our binding model.

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Inhibitors of phenylethanolamine N-methyltransferase devoid of α2-adrenoceptor affinity

Cited by 33 publications

References 27 publications

Application of the Goldilocks Effect to the Design of Potent and Selective Inhibitors of Phenylethanolamine N-Methyltransferase: Balancing pK_a and Steric Effects in the Optimization of 3-Methyl-1,2,3,4-tetrahydroisoquinoline Inhibitors by β-Fluorination

Application of the Goldilocks Effect to the Design of Potent and Selective Inhibitors of Phenylethanolamine N-Methyltransferase: Balancing pK_a and Steric Effects in the Optimization of 3-Methyl-1,2,3,4-tetrahydroisoquinoline Inhibitors by β-Fluorination

Synthesis of 4,5,6,7-tetrahydrothieno[3,2-c]pyridines and comparison with their isosteric 1,2,3,4-tetrahydroisoquinolines as inhibitors of phenylethanolamine N-methyltransferase

Mutagenic Analysis of hPNMT Confirms the Importance of Lys57 and the Inhibitor Binding Site

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Inhibitors of phenylethanolamine N-methyltransferase devoid of α2-adrenoceptor affinity

Cited by 33 publications

References 27 publications

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 β-Fluorination

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 β-Fluorination

Synthesis of 4,5,6,7-tetrahydrothieno[3,2-c]pyridines and comparison with their isosteric 1,2,3,4-tetrahydroisoquinolines as inhibitors of phenylethanolamine N-methyltransferase

Mutagenic Analysis of hPNMT Confirms the Importance of Lys57 and the Inhibitor Binding Site

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Application of the Goldilocks Effect to the Design of Potent and Selective Inhibitors of Phenylethanolamine N-Methyltransferase: Balancing pK_a and Steric Effects in the Optimization of 3-Methyl-1,2,3,4-tetrahydroisoquinoline Inhibitors by β-Fluorination

Application of the Goldilocks Effect to the Design of Potent and Selective Inhibitors of Phenylethanolamine N-Methyltransferase: Balancing pK_a and Steric Effects in the Optimization of 3-Methyl-1,2,3,4-tetrahydroisoquinoline Inhibitors by β-Fluorination