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15Phenols
Phenol has been used as antiseptic since 1867, when Joseph Lister, professor ofsurgery at the University of Glasgow, published his first article on the use of phenolin ‘‘antiseptic surgery.’’ The antiseptic properties of phenol had, however, alreadybeen noticed by the discoverer of phenol (‘‘carbolic acid’’), Friedlieb Runge, in 1833.Today, phenol and low-molecular-weight phenols are important antiseptics usedin numerous products, such as toothpaste, soap, and other detergents [1]. Otherimportant drugs containing a phenol substructure are antipyretics (paracetamol),steroids, and analogs of catecholamines [2] (see also Table 15.1).
The most common metabolic transformation of phenols is O-glucuronidationand O-sulfation. If the 2- or 4-position of a phenol is unsubstituted, aromatichydroxylation may occur. Phenols with hydroxyl, alkoxy, or amino group in orthoor para position may be oxidized to quinones. The kinetics of these processes varywidely and are difficult to estimate. Some examples of phenol metabolism areshown in Scheme 15.1.
HOH H
H
OH
Ethinyl estradiol t1/2 10 h, F 51%
hydroxylation
Propofolt1/2 0.5−1.0 h, F <5%
OH
hydroxylation glucuronidation
OH
NH
O
Acetaminophen (paracetamol) t1/2 2 h, F 88%
glucuronidationsulfation
N
OO
R-SH: glutathione, proteins
R-SHOH
NH
O
SR
CYP450
Scheme 15.1 Metabolism of phenols.
Some catechols (1,2-dihydroxybenzenes) can be methylated at high rates bycatechol-O-methyltransferase (COMT). This is the reason for the short half-livesof dopamine, adrenaline, isoproterenol, and related catecholamines. By replacingthe catechol substructure with 1,3-dihydroxybenzene, the plasma half-life of such
Lead Optimization for Medicinal Chemists: Pharmacokinetic Properties of Functional Groups and OrganicCompounds, First Edition. Florencio Zaragoza Dorwald. 2012 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2012 by Wiley-VCH Verlag GmbH & Co. KGaA.
15 Phenols 83
phenols can be significantly prolonged. Electron-withdrawing substituents mayalso block methylation of catechols by COMT [3], as does the nitro group in theCOMT inhibitor entacapone (Scheme 15.2).
HO
HOOH H
N
Isoproterenolt1/2 3 min, F 25%
HOOH H
N
Orciprenalinet1/2 2−6 h, F 10−40%
OH
HO
Entacaponet1/2 2−4 h, F 25−36%
NO2
HOCN
N
O
Scheme 15.2 Dihydroxybenzenes as drugs.
Simultaneous dosing of a COMT inhibitor, such as entacapone, is anotherstrategy to increase the half-life of catechols. The effect of levodopa (treatment forParkinson’s disease) can be prolonged by the peripheral decarboxylase inhibitor car-bidopa (Scheme 15.3). The latter suppresses the peripheral conversion of levodopainto dopamine, so that larger quantities of levodopa can reach the CNS, wheredecarboxylation to dopamine occurs. Both the absorption from the small bowel andthe crossing of the blood–brain barrier (bbb) of levodopa are mediated by an activetransport system for aromatic amino acids. Carbidopa does not cross the bbb.
CO2H
NH2
HO
HO
Levodopat1/2 1.4 h, F 41%
CO2HHO
HO
Carbidopat1/2 2.1 h, F 40−70%
NHH2N
Scheme 15.3
If a metabolically labile phenol is important for biological activity of a lead, thearomatic hydroxyl group may be replaced by a bioisostere. Phenol bioisosteresinclude benzpyrazoles, benzimidazoles, anilines, sulfonamides of anilines, andsometimes fluorobenzenes. The half-life of the vasodilator bamethan can, forinstance, be significantly enhanced by replacing the phenolic hydroxyl group by amethanesulfonylamino group or an amino group (Scheme 15.4).
Sotalolt1/2 12 h, F 90−100%
NH
OH HN
SO O
HN
HO
OH
Bamethant1/2 2.5 h, F 75%
HN
OH
H2N
Cl
ClClenbuterol
t1/2 34 h, F 89−98%
Scheme 15.4 Bioisosteres of phenols.
84 15 Phenols
References
1. Sneader, W. (1995) Antiseptics I. Drug News Perspect., 8, 504–508.2. Sneader, W. (1996) Antipyretic analgesics. Drug News Perspect., 9, 61–64.3. Bird, T.G.C., Arnould, J.C., Bertrandie, A., and Jung, F.H. (1992) Pharmacokinetics of
catechol cephalosporins. The effect of incorporating substituents into the catechol moiety onpharmacokinetics in a marmoset model. J. Med. Chem., 35, 2643–2651.
Table 15.1 Phenols and related compounds. V in l kg−1; CL in ml min−1 kg−1; Mwt in g mol−1.
t1/2 1–5 h V – PHENOLF 90% CL – Topical anesthetic andpb – Mwt 94.1 antisepticur 52% PSA 20.2 A2 Metabolism:
log P 1.54 glucuronidation, sulfation
OH
t1/2 0.5–1.0 h V 3–14 PROPOFOLF <5% CL 19–33 Anesthetic; Metabolism:pb 96–99% Mwt 178.3 aromatic hydroxylationur <0.3% PSA 20.2 A2 (position 4), sulfation,
log P 3.66 glucuronidation; Prodrug: fospropofol
OH
t1/2 0.8–0.9 h∗ V 0.33 FOSPROPOFOLF – CL 4.3–6.0 ∗ivpb 98% Mwt 288.3 Prodrug of propofolur <0.02%∗ PSA 85.8 A2
log P 2.70
O OP
OH
O OH
t1/2 27–35 h V 0.35 PENTACHLOROPHENOLF 91%∗ CL 0.02 ∗ratpb >96% Mwt 266.3 Insecticide, herbicideur 74% PSA 20.2 A2 Metabolism:
log P 5.12 glucuronidation
OH
Cl
ClCl
ClCl
t1/2 2.0±0.4 h V 0.95±0.12 ACETAMINOPHEN, PARACETAMOLF 88±15% CL 5.0±1.4 Analgesic, hepatotoxicpb Negligible Mwt 151.2 Metabolites: O-glucuronide,ur 3±1% PSA 49.3 A2 O-sulfate, quinoneimine,
log P 0.48 conjugate with glutathione
OH
NH
O
85
t1/2 0.7–1.5 h V 1–2 PHENACETINF Low CL ∗ ∗equal to hepatic blood flowpb 33% Mwt 179.2 Analgesic; extensive first passur 0.1% PSA 38.3 A2 metabolism (O-deethylation,
log P 1.66 N-deacetylation, N-hydroxylation);withdrawn in 1983 because ofhepatotoxicity
O
NH
O
t1/2 3 h∗ V – DILOXANIDE FUROATEF 60–90%∗ CL – ∗phenol on oral dosing of esterpb – Mwt 234.1 Amebicide; Metabolism:ur – PSA 40.5 A2 ester hydrolysis, then
log P 1.67 glucuronidation
O
NH
OCl
Cl
O
O
t1/2 1.8±0.6 h V 1.1±0.2 EDROPHONIUMF Low CL 9.2±3.2 Cholinergic, antidote to curarepb Low Mwt 166.2ur 65% PSA 20.2 A2
log P −2.07
OHN
t1/2 36 h (iv) V 30 TEBUFELONEF 100% (rat) CL 9.9 Antiinflammatory, hepatotoxicpb – Mwt 300.4ur – PSA 37.3 A2
log P 5.8OH
O
t1/2 100–112 h V – DARBUFELONEF 99% (rat) CL – Antiinflammatorypb – Mwt 332.5ur <0.2% PSA 101 A2
log P 4.74
OHS
N
O
H2N
t1/2 1.1–1.3 h V 0.12 TOLCAPONEF 60–72% CL 1.7–1.9 COMT inhibitor, antiparkinsonianpb 99.8% Mwt 273.2 Metabolism: glucuronidation,ur 0.5% PSA 103 A2 O-methylation of 3-hydroxy,
log P 4.15 reduction of nitro to amino,hydroxylation of methyl, oxidation ofmethyl to CO2H
OOH
OH
NO2
t1/2 4 h V – NEBICAPONEF >55% (rat) CL – COMT inhibitorpb >99% Mwt 273.2 Metabolism: glucuronidation,ur <1% PSA 103 A2 O-methylation
log P 3.84
OOH
OH
NO2
(continued overleaf )
86 15 Phenols
t1/2 2.4–3.5 h V 0.28 ENTACAPONEF 25–36% CL 12 COMT inhibitor; antiparkinsonianpb 98% Mwt 305.3 Metabolism: E to Z isomerization,ur <0.5% PSA 130 A2 glucuronidation, hydrogenation,
log P 2.38 and cleavage of C=C double bond
OH
OH
NO2
CNN
O
t1/2 7 h V 0.9 (rat) NICLOSAMIDEF 10% (rat) CL 20 (rat, iv) Anthelminticpb – Mwt 327.1 Metabolism: glucuronidationur – PSA 95.2 A2
log P 3.77
NH
OO2N
Cl
OH
Cl
t1/2 22 h V – EZETIMIBEF Unknown CL – Oral antilipemic; activepb 99.7% Mwt 409.4 metabolite: phenol glucuronideur 2% PSA 60.8 A2 Further metabolism: oxidation of
log P 3.96 secondary alcohol to ketoneOH
N
O
F
F
OH
t1/2 32±12 h V 8.9±4.2 DRONABINOL, THCF 8±4% CL 3.5±0.9 Antiemetic, appetite stimulantpb 95% Mwt 314.5 Active metabolite: 11-hydroxyur <1% PSA 29.5 A2
log P 6.84O
OHH
H
t1/2 2 h V 12.5 NABILONEF 20% CL 0.7 Antiemeticpb – Mwt 372.5 Metabolism: reduction of ketone tour 22% (iv) PSA 46.5 A2 alcohol,
log P 7.25 hydroxylation at CH2CH3O
O
OHH
H
t1/2 81±19 h V – D-α-TOCOPHEROLF 35–85% CL – Vitaminpb – Mwt 430.7 Prodrug: acetateur <1% PSA 29.5 A2
log P 11.0
OH
O
t1/2 <6 h V – BISPHENOL AF Low CL – Monomer for polycarbonates andpb – Mwt 228.3 epoxy resins, fungicideur – PSA 40.5 A2 Metabolism: glucuronidation
log P 3.64
OHHO
87
t1/2 6–44 h V – HEXACHLOROPHENEF – CL – Antiseptic, disinfectantpb 92% Mwt 406.9ur – PSA 40.5 A2
log P 7.17OHOH
Cl Cl
Cl Cl
ClCl
t1/2 1.2 h V – CLOFOCTOL, OCTOFENEF High CL – Antibioticpb – Mwt 365.3 Metabolism: glucuronidationur – PSA 20.2 A2
log P 8.25OH Cl
Cl
t1/2 18–29 h∗ V – CYCLOFENILF – CL – ∗diphenol on oral dosing ofpb – Mwt 364.4 diacetate; gonad-stimulatingur 0% PSA 52.6 A2 principle; withdrawn because
log P 4.66 of hepatotoxicity
OO
O O
t1/2 28 h V 5∗ DIETHYLSTILBESTROLF – CL – ∗monkey; Estrogen; Metabolism:pb 50–95% Mwt 268.4 aromatic hydroxylation to catechol,ur – PSA 40.5 A2 hydroxylation of methyl groups;
log P 5.33 withdrawn in 1975 as it causesadenocarcinoma of vagina in daughtersafter use in early pregnancy
OH
HO
t1/2 23–47 d V – PROBUCOLF 2–8% CL – Hypolipidemic; poor absorbtionpb – Mwt 516.8 (1–14%) because of poor solubilityur <2% PSA 91.1 A2 Metabolism: oxidative cyclization
log P 9.00 to dispiroquinone (bond formationbetween the 4-positions of thephenols), then formation of sulfur-freediphenoquinone
SS
HO OH
t1/2 28±9 h V 1.0±0.1 DAPSONEF 93±8% CL 0.60±0.17 Antibacterial (leprostatic)pb 73±1% Mwt 248.3 Metabolism: N-hydroxylation,ur 15% PSA 94.6 A2 N-acetylation; causes
log P 0.99 methemoglobin formation andhemolysis
SOO
H2N NH2
t1/2 3–8 h V – SULFOXONEF – CL – Antibacterial (leprostatic)pb 69% Mwt 404.5 Metabolism: hydrolysis to dapsoneur – PSA 180 A2
log P −1.91
SOO
NH
NH
SSHO O OHO
(continued overleaf )
88 15 Phenols
t1/2 14±2 h∗ V – BENZARONEF – CL – ∗after oral administration ofpb >99% Mwt 266.3 benzbromaroneur – PSA 50.4 A2 Capillary protectant
log P 4.73 Metabolism: O-sulfation,O-glucuronidation, ethyl hydroxylation;no unchanged benzarone can bedetected in plasma after oraladministration
OH
O
O
t1/2 3±1 h V 19 BENZBROMARONEF – CL – Uricosuric, hepatotoxicpb >99% Mwt 424.1 Metabolism: debromination tour 0% PSA 50.4 A2 benzarone
log P 6.65OH
O
O
Br
Br
t1/2 10 h V – IPRIFLAVONEF 24% (rat) CL – Treatment of osteoporosispb – Mwt 280.3 Metabolism: phenylur PSA 35.5 A2 4-hydroxylation,
log P 4.25 O-deisopropylationOO
O
t1/2 8 h V 3–5 DAIDZEINF 2–10%∗ CL 7.7 ∗ratpb – Mwt 254.2 Natural isoflavone, phytoestrogenur 30–50% PSA 66.8 A2 Metabolism: glucuronidation,
log P 2.63 sulfationOHO
OHO
t1/2 10 h V 2.5 GENISTEINF 20–40%∗ CL – ∗ratpb – Mwt 270.2 Natural isoflavone: phytoestrogenur 9% PSA 87.0 A2 Metabolism: glucuronidation,
log P 3.11 sulfationOHO
OHOOH
t1/2 0.6 h (iv) V 0.1 QUERCETINF <1% CL 11 Capillary protectantpb 99% Mwt 302.2ur 0.5% PSA 127 A2
log P 1.99O
OH
HO
OOH
OH
OH
t1/2 5 min V – FLAVOXATEF 100% CL – ∗acidpb 99.5%∗ Mwt 391.5 Antispasmodic: does not cross bbbur 0% PSA 55.8 A2 Metabolism: hydrolysis of ester
log P 4.27O
O
O O
N
89
t1/2 0.7 h (iv) V – IDRONOXILF 1% CL – Proapoptotic agent: oncolyticpb – Mwt 240.3ur 0% PSA 49.7 A2
log P 3.35OHO
OH
t1/2 short V – CURCUMINF 0% CL – Natural dye and antioxidantpb – Mwt 368.4 Metabolism: glucuronidation,ur 0% PSA 93.1 A2 sulfation, hydrogenation of C=C
log P 3.07 double bonds, reduction of ketoneto alcohol
O OH
HO OH
OMeMeO
t1/2 12 h V – ALIZARINF – CL Biological stainpb – Mwt 240.2 Metabolism: O-glucuronidationur 18–36% PSA 74.6 A2
log P 2.91
O
O
OHOH
t1/2 4–8 h∗ V – DIACEREIN, DIACETYLRHEINF 35%∗ CL – ∗rhein on oral dosing of diacereinpb 99%∗ Mwt 368.3 Antiarthriticur 20%∗ PSA 124 A2 Metabolism: deacetylation to rhein,
log P 3.13 then glucuronidation, sulfation
CO2H
OO O
O
O O
t1/2 8±4 h V 0.36±0.15 ETOPOSIDEF 52±17% CL 0.68±0.23 Antineoplasticpb 96±0.4% Mwt 588.6ur 35±5% PSA 161 A2
log P 0.28
O
O
OO
OHO
O
OH
O
O
OHOMeMeO
(continued overleaf )
90 15 Phenols
t1/2 9±3 h V 0.22±0.05 TENIPOSIDEF 20–71% CL 0.37±0.13 Antineoplasticpb 99% Mwt 656.7 Metabolism: O-demethylationur 8±2% PSA 189 A2
log P 1.56
O
O
OO
OHO
O
OH
O
O
OHOMeMeO
S
t1/2 2–12 h V 0.3 NK-611F 100% CL 0.4 Antineoplasticpb 99% Mwt 615.6 Metabolites: N-desmethyl, cis-lactoneur 3–26% (iv) PSA 143.9 A2
log P 1.14
O
O
OO
NO
O
OH
O
O
OHOMeMeO
t1/2 25–27 h V 0.25 HYPERICINF – CL 0.13 Antidepressant, phototoxicpb – Mwt 504.4 component of St. John’s wortur – PSA 156 A2 Metabolism: negligible
log P 10.8
O
OOH
HO
OH
OHOH
HO
t1/2 16–36 h V 0.56 PSEUDOHYPERICINF – CL 0.62 Dye from Hypericum perforatumpb – Mwt 520.4 (St. John’s wort)
ur – PSA 176 A2
log P 9.29
O
OOH
HO
OH
OHOH
HO
OH
t1/2, plasma half-life; F, oral bioavailability; pb, plasma protein binding; ur, excretion of unchangeddrug in urine; V, volume of distribution; CL, clearance; Mwt, molecular weight; PSA, polar surfacearea; THC, tetrahydrocannabinol.
