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`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
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`ELSEVIER European Journal of Pharmaceutical Socnces 2 (19941 373-384 EUROPEAN JOURNAL OF PflARMACE[TICAL SCIENCES Lipophilicity and hydrogen-bonding capacity of Hi-antihistaminic agents in relation to their central sedative side-effects A.M. ter Laak", R.S. Tsai b, G.M. Donn6-Op den Kelder ", P.-A. Carrupt b, B. Testa b, H. Timmerman "* "Leiden~Amsterdam Center for Drug Research. Dept of Pharmaeochemtsto'. Faculty of Chemistry. Vrqe Umversttett. de Boelelaan 1083, 1081 HV Amsterdam. Netherlands "lnstttut de Chtmte Th~rapeuttque. l".cole de Pharmacte. Umt,erstte de Lausanne. BEP. CH-IOI5 Lausanne. Switzerland Recewed 16 March 1994; accepted 22 July 1994 Abstract Modern non-sedating histamine Hi-receptor antagonists (e g terfenadme, temelastme, cetmzme, astemizole) are considered to be devoid of CNS side-effects because, as a result of their physicochemlcal properties, they do not cross the blood-brain barrier (BBB) in sufficient amounts. In the present study lipophihoty parameters considered to be of importance for brain penetration capability (such as log Poe,, log D .... 7 4, A log P and ^.tk..~) were determined for a series of structurally different sedating and non-sedating histamine H ~-receptor antagonists These parameters were obtained from log P., and log P.~k values measured by centrifugal partition chromatography (CPC), a new and efficient method for measuring partition coefficients. From the lipophilicity data obtained it appears that the (non)-sedatwc effects of antihistamines cannot be correctly accounted for by brain penetration models that use only H-bonding (A log P) or hydration capacity (^,,~k~.L.) as a parameter Indeed, in this series of usually basic Hi-blockers. ionization also appears to play an important role. We conclude that sedative effects displayed by antihistamines are better explained by the parameter log D ..... ~ 4. the octanol/water distribution coefficient of both neutral and iomzed species at pH 7 4. For neural organic compounds it was found that brain penetration ts highest if they have a log P,,~, value of approximately 2 ('principle of minimal hydrophobloty') Our data suggest that this principle is also applicable to lomzable drugs when log D ..... 7. is used instead of log P,,~, A tentative qualitative model for designing antihistamines without CNS side-effects is presented. Keywords: Histamine HI-receptor blockaders; Sedation; Central nervous system List of abbreviations BBB CNS P D oct alk dod A log Poet ,,*k VM A alkane blood-brain barrier central nervous system partition coefficient distribution coefficient octanol/water alkane/water dodecane/water log Poc, minus log P, lk molecular Van der Waals volume molar volume a measure of hydration capacity *Corresponding author Tel. (+31-20) 4447580, Fax (+31-20) 444761(I. 0928-0987/94/$(17 00 © 1994 Elsevier Science B V All rights reserved SSDI (1928-(1987( 94 )00(165-4 1. Introduction 1.1. Sedative side-effects and brain penetration of histamine H l-receptor antagonists One major drawback of the classical histamine- H l antagonists has been their induction of CNS side-effects (most importantly scdation) at doses lower than needed for optimal therapeutic effect. Various studies suggest that these sedative side- effects are associated with blockade of central histamine-H I receptors (Quach ct al., 1979; Uzan et al., 1979; Hall and Ogren, 1984; Nicholson et al., 1991). Particularly relevant in this respect are the studies in man with the enantiomers of chiorpheniramine and dimethindene, sedative effects being shown to be limited to the enantio- mers with high histamine Hi-receptor affinity
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`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
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`374 .,I .'U ter l.aM, cl al l:utopean Joutmd o! t'hatma~{'tttt~ al .~ a'm~'~ 2 (Iq~)41 .;~.~ ;N4 (Nicholson el al.. 1991). This strongly suggests that sedation could arise from I-I~-receptor an- tagonism alone. However, antagonism to other CNS receptors such as serotonin, acetylcholinc or a-adrencrgic receptors by classical and possibly less selective antihistamines could contribute to the sedative effect. It has been claimed in the hterature that non- sedative H ~-blockcrs such as loratadine (Ahn and Barnett. 1986) and mequitazlnc (1.eFur ct al.. 1981) have higher affinity for peripheral than tk)r central I{~-receptors. ttowever, this selectivity appears to be far too low to explain the advan- tageous ram-sedating properties of these com- pounds. Moreover. m a recent study on a series of classical sedating and modern non-sedating antlhlstalnines (including terfenadine, astemizole, Ioratadtne. epinastinc, temelastine and cetiri- zinc), no differences were found m the aftinitv for peripheral and CNS H,-receptors (Tcr Laak et al.. 1993). Therefore. it is more likely that the non-sedative behaviour of modern H~-receptor antagonists is caused by specitic molecular prop- erties preventing these molecules from crossing in sufficient amounts the blood-brain barrier (BBB). Indeed. various studies have indicated that non-sedating antihistamines do not reach thc bram or do not occupy CNS H~-receptors in vlvo. This has been demonstrated for terfcnadine (Sor- kin and Heel. 1985: Rose et at.. 1982; Barnett et al.. 1984). loratadine (Barnett et al.. 1984). astemizole (Laduron et al.. 1982: Barnett et al.. 1984). temelastlne (Calcutt et al.. 1987) and epinastine (Fugner et al.. 1988). It is generally believed that for the passive transport of solutes across biomembranes, and particularly for crossing the blood-brain barrier. a rehltively high hpophilicity is needed. However, preliminary hpophllicity estimates on some sedat- ing and non-sedating antihistamines revealed that lipophlhclty conventionally expressed as the partition coefficient in an octanol/watcr system (log P.,) cannot solely account for diffcrcnccs in CNS pcnetrauon bchaviour; other factors seem to be involved. 1.2. Brain penetratton models In the literature various relanonships have been reported which relate lipophiliclty and/or molecular size with BBB passage. One of the most common parameters used to exphun the brain penetration of neutral organic compounds is log P,~,. I.evin (1980) derived a quantitative relationship between the permeability coefficient PC (related to CNS entry), log P,~, and molecular wmght MW for a series of structurally diverse compounds of relatively low molecular weight ( MW < 400): log PC = -4.606 + 0.4115 log [Po~,(MW)-' :] (n = 22, r = 0.95) (1) Hansch and co-workers (1987) improved Eq. 1 tO: log PC = 0.50 log P,~, - 1.43 log MW - 1.84 (n=23. r=0.96) (2) but also studied different sets of compounds (hypnotics. aliphatic ethers, imidazolidine deriva- tives and tricyclic antidepressants) for which in general parabohc equations were derived with an optimal log P,,,., value of about 2: log BBB penetration = a log P,~, - b log P~., + c (3) A satisfactory explanation for this parabohc be- haviour was given many years ago by the non- steady-state theory of Penniston el al. (1969). In their theoretical multi-compartment model the membrane is simulated as a single compartment of lipid character without specltic structural fea- tures. The resulting biphasic curves approxunatc the experimentally observed lipophiliclty-pcnc- tratlon relationships extremely well. Most im- portantly, the validity of the above non-steady- state model was later contirmcd experimentally with a physical multi-cell system in a study by Dcarden and Patel (1978). For the particular case of umizablc drugs Hansch ct al. (1987) suggested to use the dis- tribution coefficient at pH 7.4 (log D,~,) instead of the partition coefficient of the neural species (iogP,,,.,). LogD,~,~ is a function of the logP and pK, values of the compound and therefore imphcates two molecular features: the percentage of uncharged species of the compound at physio- logical pH (pK,,) and the abilitv of this uncharged species to partition into a hpophilic phase (Iog P,~¢). For mono-protm bases these two pa- rammers are related to log D,~,:
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`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
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`A M ter Laak et al / European Journal of Pharmaceutwal Sctences" 2 (1994) 373-384 375 log Doer, 7 4 : log P,,c, - log (1 + 10 'pK''-7 4)) (4) A parabolic equation describing the transport across the blood-brain barrier for a series of 14 basic imidazolidines is given by Timmermans et al. (1977): L°g(Ct ...... /Cblood) = 0.57 log D,,,.t. 7 4 - 0.13 log D~,c,.7 a - 0.09 (n = 14, r = 0.987) with an optimal log D,,,.,. 7 4 of 2.16 (5) The similarity between Eq. 3 and Eq. 5 sug- gests that under physiological conditions the protonated species of an ionizable drug does not contribute significantly to the partitioning of the drug into and across biomembranes, or to the partitioning into other lipophilic compartments (e.g. non-specific binding to serum proteins such as albumin, og-acid glycoprotein or lipoproteins (Kristensen and Gram, 1982)). It was reported only recently that the hydro- gen-bonding ability of solutes can be a structural determinant for brain penetration. For a series of histamine H2-antagonists a satisfactory relation- ship between hydrogen-bonding capacity and brain penetration was established by Young et al. (1988). High hydrogen-bonding capacity corre- lated with low brain penetration capacities ac- cording to the equation: log (C~r,,,°/Ct, t,,,,d ) = -0.485 A log P,,ct-;,k +0.889 (n=20, r=0.831) (6) where the parameter A log P,,c,-,~k is a descriptor for hydrogen-bonding capacity (Seiler, 1974; El Tayar et al., 1992). Van de Waterbcemd and Kansy (1992) rein- vestigated the same series of H2-antagonists previously studied by Young et at. (1988) re- sulting in: log (C b ..... /Cb,,,,j) = --0.338 ^ ,,k,,.~ + 0"007Vm + 1.730 (n = 20, r = 0.934) (7) in which V M presents the molar Van der Waals volume and A=,~k..~ is a descriptor for hydration capacity, or with A alkane alone: log (C, ..... /Cb,,,,~ ) = -0.208^ ~lk..~. + 2.301 (n = 19. r = 0.839) (8) 1.3. Present study Based on the indications that the non-sedative behaviour of modern antihistamines is generally accompanied by a low ability to penetrate into the CNS, we decided to determine lipophilicity parameters for a series of 20 structurally different sedating and non-sedating Hi-antihistamines (Fig. 1) in two different solvent/water systems. To achieve this we used centrifugal partition chromatography (CPC), an efficient and highly accurate technique for measuring distribution coefficients in different organic solvent/water systems (El Tayar ct al., 1991). Our study aims at improving the understanding of the mfluence of lipophilicity (log P, log D 7 4), hydrogen bond capacities (J log P) and/or hydra- tion capacities (A,, k ..... ) on brain penetration in general but more specifically on the central side- effects of histamine H t-receptor antagonists. Since we intended to study a series of structurally diverse antihistamines and because for most compounds quantitative brain penetration data are not available, quantitative structure-permea- tion correlations are not possible. Instead. for the purpose of designing non-sedating antihistamines without central side-effects, a generalized quali- tative lipophilicity model is presented. 2. Experimental procedures 2.1. Materials Pyrilaminc maleate (mepyramine (4)) was ob- tained from Sigma Chemical Company (St. Louis, USA). The following drugs were kindly donated by the indicated institutions: (S)-(+)- chlorpheniramine malcatc (2) from A. Beld (University of Nijmcgen, Nijmegen, Nether- lands), (-)-cicletanide (20) from the Institut Henry Beaufour (Le Plessis Robinson, France), (R)-(-)-dimcthindene (7) from U. Borchard (University of Dfisseldorf, Diasseldorf, Ger- many), imipramine (1), diphenhydramine HCI (3), azatadinc (5), (R)-(+)-terfenadine (13) and terfenadine analogues (14-18) (Zhang ct al., 1993) from our own laboratory stock, astcmizole (11) from Jansscn Pharmaceutica NV (Bccrse, Belgium), epmastine HCI (WAL801 CL (12)) from Bochringer-Ingelheim (Ingelheim, Ger- many), Ioratadinc (8) (SCH29851) and dcscar- boxyethylioratadine acetate (SCH34117 (19))
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`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2070 - 9/18
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`37(~ A M ter Laak ct ul European Journal ol I'harmaccutual St,.nte.s 2 (19941 .~Z~-3,'~'4 7 NC Cll~ ,__._/ CII~ tmlpramme (1) CH3 ol, llC* o'CHI'CHI'N O ' CIt 5 diphenhydramine (3) ~ - Cl Ij azatadine (5) CI 0C}Ij HC ~c"t t ,.O]~.N CN ~t, chlorpheniramine (2, pK, =8 32) H3CO ~ O{~ ~ CH3 N~CH2 CIIH~ CN CH3 o mepyramine (4, pK~=8.94) HC*~N N"X /--- CH~ hydroxyzine (6) /CII3 CII2 CH~-N x CH3 N llC*~ dimethmdene (7, pKl=9.21) CI -% 13 loratadine (8, pK,=6.81) ~N rlm C'tl 2 F astemizole (11, pKt=8.28) c~ ~ .9 IIC* cetinzine (9, pK,--7.53) d./N epinastine (12, pKc-8.85) Br ~CH~ O H H temelastine (10, pK,=8.79) ~ x._.j x....J ~ ~t3 terfe~adine (13, pKi=7.13) It HO c.,~ ~ /"'~ ~ /=N ,;,.3 tlO - "C '=~ N "X C* "~. ]tx---='~ CI:I 3 O X...J X...J ~ 6H3 (14, pK,=6.00) (16, pK,=6A9) cl Nql descarboxyethyl-loratadine (19, pK,=8.39) O l.../ X._/ ~ ~q (15, pKi---6.78) (17, pK,=7.40) CH 3 OH Cl ci¢letanide (20, pKs=7.54) (18, pK,=7.42) Fig 1 Structural formulas of H:antagomsts considered tn this study Compounds 1 to 7 are known as H,-antagomsts with scdauvc side effects Compounds 8 to 13 are reported as non-sedatwe H,-antagomsts For compounds 14 to 20 we have no information on brain penetration Apparent pK values measured m vitro on guinea pig cerebellum (Ter [+aak et al . 19931 ,arc mentioned between parentheses
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`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2070 - 10/18
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`A M ter Laak et al / European Journal of Pharmaceuttcal Sctences 2 (1994) 373-384 377 from Schering Co. (Bloomfield, USA), hydroxyzine.2HCl (6) and cetirizine HCI (9) from UCB (Braine-d'Alleud, Belgium) and temelastine (10) (SKF93944) and icotidine (SKF 93319) from SmithKline Beecham (Welwyn Gar- den City, UK). Analytical grade n-dodecane was purchased from Aldrich-Chemic (Steinheim, Germany), and analytical grade 1-octanol was obtained from Fluka Chemika (Buchs, Switzer- land). The aqueous buffers used for CPC mea- surements were 0.02 M MES-buffer (2-(N-mor- pholino)ethane-sulfonic acid, Calbiochem, La Jolla, California, USA) for pH range 1.5-5.0, or 0.02M MPS-buffer (3-morpholinopropane sul- fonic acid, Merck, Darmstadt, Germany) for pH range 5.5-7.5. These zwitterionic buffers could minimize the contribution to distribution coeffi- cient of ion-pairs when the solute is in an ionized state in the aqueous phase. 2.2. pK, measurements The pK;~ values listed for basic compounds 1-6 (the alkylated nitrogens) were taken from the literature (Hansch et al., 1990). Potentiometric titrations of compounds 7, 9, 14, 18, 19 and 20 were performed with a Metrohm titroprocessor Model 670 (Herisau, Switzerland) using a solute concentration of 10-3-10 4M in 0.1 M KC! and 0.01 N NaOH as the titrant. The temperature of the titration cell was maintained at 25-+0.1°C, and the cell was refluxed with nitrogen gas. The pK, values were calculated from a non-logarith- mic linearisation of the titration curve (Leeson and Brown, 1966). For three compounds (14, 18 and 20) 2% ethanol had to be added because of their low solubility. For terfenadine (13) and its analogues 15-17, accurate pK, values were dif- ficult to obtain due to their limited solubility in water. In these cases the pK a of the least lipo- philic but structurally comparable analogue 18 was used to calculate log P. For the multiprotic compounds 10,11 and icotidine and for the highly basic compound 12, the pK~ values were determined using the Sirius PCAI01 apparatus (East Sussex, UK) equipped with a semi-micro combination pH electrode (Orion 8103SC), a temperature probe, an over- head stirrer, a precision dispenser and a six-way valve for distributing reagents and titrants (0.5MHCI, 0.1MKCI and 0.5MKOH). A weighted sample (1-10 mg) was supplied manual- ly, the diluent and all other reagents added automatically. Bjerrum plots were used to calcu- late precise pK, values (Avdeef et al., 1982). The detailed experimental procedures and data analy- ses have been described elsewhere (Avdeef, 1992). This novel technique appears to overcome the problem of overlapping pK, values. The pK, of Ioratadine (8) was calculated from the log Pd,,d value (2.40) measured by CPC at pH 7.40 and a log D,j,, o value (0.90) measured at pH 3.09 (not in Table 1) via the equation log P = log D + log (1 + 10~P~-rHJ). 2.3. Partition coefficient measurements using centrifugal partition chromatography Centrifugal partition chromatography (CPC) is a chromatographic technique which uses two poorly miscible liquids as mobile and stationary phases (El Tayar et al., 1991). The partition coefficient in the biphasic system is accurately calculated from the chromatographic retention parameters. The advantages of this method are that it has efficient mixing mechanisms between the two phases and is devoid of a solid support (as in e.g. RP-HPLC) (lto, 1988). Consequently, the partition coefficient depends only on solute- solvent interactions and is not perturbed by specific interactions with a solid support material. Partition coefficient measurements were thus performed with a horizontal flow-through multi- layer centrifuge (model CCC1000, Pharma-Tech Research, Baltimore, USA, volume capacity 326 ml) which is of coil planet type and equipped with PTFE-tubing (polytetrafluoroethylene, 3.00 mm I.D., 3.94 mm O.D.). The mobile phase was propelled with a Kontron model 420 HPLC pump and the eluate was detected with a Kon- tron model 432 UV detector. Dodecane was used for the measurement of log Pa~k values as m our experience the dodecane/water system does not form air bubbles in the detector cell as often observed with other alkane/water systems. It should be mentioned that differences between Iog P,~ k values measured in different alkane/ water systems (e.g. cyclohexane, n-heptane or n-dodecane) are negligible (Seiler, 1974). De- pending on the estimated value of the partition coefficient, the volume ratio of stationary and mobile phases was adjusted (36:1-3.1) by chang- ing the flow rate (0.5-3.0 ml/min) or the rotation speed (800-900 rpm). Chromatograms were re-
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`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2070 - 11/18
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`37."; A .~1 tet l.aak et al . l-urolwan Jo.rnal Ol l'hurmu~ eutu ul g~ writes 2 (19q.4) .;73-.3S4 Table 1 pK and hpophdicity parameters of H,-antagomsts pK log D ..... log D,,,.~ log P,,,, log P~,,, g log P .... ,k Vw A.,,~ log t) .... ., (1) tm~pramme 9 5 2 35 1 88 4 44 3 98 tl 46 293 8 7 41 2 33 (2) chlorphemramme 9 16 1 42 0 32 3 17 2 1)9 1 08 270 4 8 42 1 4(I (3) diphenhydrammc 8 98 1 60 0.97 3 17 2 56 () 61 268 7 7 89 I 58 (4) mepyramme 8 92 1 45 (I.47 2 96 2 D() 11 96 292 6 9 35 1 43 (5) azatadmc 9.3 1.71/ .11.1)9 3 59 1 82 I 77 293 5 9 56 I 68 (6) hydroxyzme 7 l(I I).95 (5 00) (I 91 3 05 1 09 I 96 361 4 12 84 2 87 (7) dtmethmdene 8 45 1.63 (I 56 2 70 I 65 I (15 309 7 10 34 1 61 (8) Ioratad,ne 458 1 32(1 50) 240 440 240 200 3498 11.10 440 (9) cctmzme 3 66,8.21 1 04 -2 83 4 48 0 61 3 87 361 4 13 32 1 04 10) temelastme 2 7.3 6.5 4 2 66 (5 00) >3 (2 00) 3 19 1 28 I 91 375 9 13 20 3 19 11) astemlzolc 5 44.6 71 1 27 (5 (1()) >3 (2 00) 3 56 I) 95 2 61 438 5 15.88 3 48 12) cpmastmc 11 5 -(168(750) >3(200) 351 1 76 1 75 2366 748 075 13) terfenadme 8 6 2 11 (5 iX)) 1 42 5 69 2 63 3 06 492 3 16.23 4 46 14) VUF4585 851 157(602) -035 4(16 079 327 4184 1529 292 15) VI.JF4591) 8 5 2 (14 - 3 25 - 486 6 15 39 - 16) VUF4591 8 6 - 3 20 - 5 30 - 485.7 13 31 - 17) VUF4592 8.6 1 86 (6 02) 1 03 4.42 2.24 2 18 419.4 13 88 3.19 18) VUF4593 858 1 34 (6 02) -0 19 3.90 1 02 2.88 4249 15 30 269 19) desc-loratadme 865 I 31 -1181 256 1146 2 111 291 8 1086 1 29 (21)) ctcletamde 3.11 2 34 --1 76 2 34 1.76 4 10 228 0 10 68 2 34 oct = octanol/watcr system, dod = dodccane/watcr system, log D = dtstnbtltlon coeflictcnt measured at pH 7 4 unless men- ttoned otherwise between parentheses, log P = partition coefficient of the neutral species: A log P, ..... ~ - log P, - log P.... V.. =Van der Waals volume: log D ..... ~ = distribution coefficient in octanol/water at pH 7 4 corded with a Hcwlctt-Packard 3392A integrator. In case of an organic mobile phase, distribution coefficients were calculated from log D = log[(V.t-V,,~)/(V R-VM) ], where V r is the re- tention volume, V- r the total volume of the column and V M the volume of the mobile phase (dead volume). Log D values that can be mea- sured using CPC lie in the range between -3 and +3. Because log D is a function of pH, log P and pK~, the pH of the aqueous phase can be adjusted so that the log D value is experimentally measurable. From the pK~, value(s) and the d~stribution coefficient, the lipophilicity parameters of the neutral species (log P,,~,. log Pd,,,J, A log P,,c,-,,~k) can be calculatcd. For compounds containing one protonated group at the applied pH (1-8 and 13-20) iog P is calculated using the standard equation (Eq. 4). For cctirizme (9) which is a zwltterion at pH 7.4, log P of the neutral cctirizine is calcu- lated from the macroscopic acidic and basic pK, values determined by titration (pK,~ =3.66, pK.,z~=8.21 ) and from the IogD at pH7.40 using the equation: log P = log D + log {1 + 1() ~pK'''-p~I~ + I()(pII-pK"2tl + K,II/K.e_~ } (9) (Tsai et al.. 1993). where K.,_,_, is the K., of hydroxyzine (6). For temelastinc (10), which is neutral at pH 7.4, log P,,~, is calculated from the three baste pK, values in the equation: log P = log D + log {1 + 1() ~K'''-Pu~ + l()(pK.,t-pK.,2.-2p11) + IOIVK,,'I,K,.'pK.,,-'OUl} (10) In a similar way the log P,,,., value of astcmizole ( I 1 ) is calculated using: log P = log D + log {i + 1() ~e~''' ~,ul + 10tV~.,,'VK.,.~ 2pJl~}. (11) Since epinastine (12) is a strong base (pK = 11.81), it is assumed that both the ion-pair and the neutral form contribute to the distribution of this compound at pH 7.50. The log P,~, value of the neutral species is calculated from: IogP=log{D+ 10 IoK.' pUlx(D_p ...... i ..... )} (12) with the log D,,. t of cpinastme measured at pH 3.6 interpreted as the log P value of the ion- pair formed between the protonated species and chloride: this interpretation seems to be valid
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`A M ter Laak et al / European Journal of Pharrnaceutzcal Sctences 2 (1994) 373-384 379 since at low pH values (3.5-5.5) the measured log D value remains constant (iog P, o,.r~,~=- 1.30, not in Table 1). For compounds 14 and 18 it was not possible to measure IOgDd,,d values with CPC because of their relatively low solubility. For these com- pounds log Ddo ~ values were therefore measured by the traditional shake-flask method with UV detection. 2.4. Potentiometric log P determination For compounds 10, 11 and 12 log Pdod values were measured with the built-in log P option of the Sirius PCAI01 instrument (East Sussex, UK). After the first titration in aqueous solution, a certain amount of dodecane is added and the biphasic solution is "back-titrated". From the difference between the two titration curves the log Pdod value can be calculated by simulation procedures (for details, see Avdeef, 1992). 2.5. Derivation of molecular parameters 2.5. I. Determination of the molecular van der Waals volume (Vw) For all compounds, the geometry was fully optimized with the Tripos force field containing electrostatic term (SYBYL molecular modeling software, version 5.41, Tripos Associate Ltd., St. Louis, Missouri, running on a Silicon Graphics Personal Iris 4D/35 workstation). Molecular vol- ume calculations were performed with the MOLSV program [QCPE, No. 509] using atomic radii described by Gavezotti (1983). 2.5.2. Determination of polarity parameters (A log P,,,,-al~ and A~lk,ne ) The descriptor of hydrogen-bonding capacity, the parameter JlogPo,.,_~,tk (Seiler, 1974), pre- dominantly reflects the hydrogen bond donor capacity of solutes, and, to a lesser extent, their hydrogen bond acceptor basicity (El Tayar et al., 1992). J log P,,~-~lk was obtained by simply sub- tracting the expcrimentally obtained IOgPdo d from log P,,~: ,.1 log Po~.t ~,k = log Po~t - log Pd,,d (13) By analogy with previous work (El Tayar et al., 1992), Aa~k~,,. which represents the sum of polar interactions of solutes with water was calculated by the equation: A .,k = log P~, .,k -- log P~×o.,,lk (14) where log Pe~t.,tk is defined as the partition coeffi- cient in an alkane/water system of an alkane having the same molecular volume as the investi- gated compound and the log P~xp,r~ is the ex- perimental value. The log Pc~t.a~ k value can be calculated by the following calibration equation, which was derived from the measured partition coefficients of simple alkanes in an alkane/water system and their molecular Van der Waals vol- umes (Vw): log Pcst.alk = 0.0376 V w + 0.346 (15) 3. Results and discussion 3.1. Properties of the investigated compounds Although no consistent quantitative data of brain penetration have been established for the 20 compounds considered in this study (e.g. by ex vivo experiments), they can approximately be divided into classical sedating Hi-blockers with high brain-penetration capacity and more recent- ly developed H,-blockers with low brain-penetra- tion capacity (Fig. 1). Compounds 1 to 7 are known as Hvantagonists with pronounced seda- tive side-effects (Pong and Huang, 1974; Tozzi, 1974: Quach et al., 1979; Hall and Ogren, 1984; Roth et al., 1987; Nicholson et al., 1991). Com- pounds 8 to 13 are reported as non-sedative Hi-antagonists with low brain penetration (Laduron et al., 1982; Sorkin and Heel, 1985; Calcutt et al., 1987; Roth et al., 1987; Fflgner et al., 1988; Clissold et al., 1989; Schilling et al., 1990; Simons, 1992). For five terfenadine ana- logues (14-18) (Zhang et al., 1993), compound 19 (Tozzi, 1974) and cicletanide 20 (Schoeffter et al., 1987), no information on sedative side-effects has been reported. In accordance with the above data, Fig. 1 was divided into 3 blocks, namely classical sedating compounds, recently developed non-sedating antihistamines and compounds for which no data on brain penetration or sedative effects are available. The experimental results are presented in Table 1. 3.2. Distribution coefficients of compounds 10- 12 For compounds 10 to 12 we were not able to measure log D values in the dodecane/water system using the CPC method. With dodecane as mobile phase, the chromatographic peaks eluted
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`38(I 4 M tet Laak et a/ l:unq~ean Journal o! I~harmaceutt( al ,g( u'm es 2 (1~94) .~z ; 384 with the solvent front even at low pH values where these compounds are almost completely protonated (pH 2.0). These findings indicate that such compounds have unreliably high log Pd,,d values (at least log P,~,,,, >3). However, with the pH-metric method log Pdo,~ values were obtained which were surprisingly low (1.28 (10), 0.95 (11) and 1.76 (12)). The observed discrepancy be- tween the two methods in measuring iogP,~,, d values for 10. II and'12 is explained by assuming that these compounds have an abnormal parti- tioning behaviour in the centrifugal force field of CPC and behave as amphiphilic surfactants. The compounds in their protonatcd state possibly form mice[les and partmon predominantly into the dodecane phase (Dearden and Bresnen, 1988). or, alternatively, into the interfacial sur- face area between the two phases. We have used log P~,,j values measured with the pH-metric method to calculate A log P,,~.,..,,k and /x.,,~ ..... for compounds 10-12. 3.3. Intercorrelation of hpophilicity parameters Before discussing ..1 log P,,c,-~k. ^,.k .... . log P,~., and log D,~. t 7 4 in relation to the observed CNS effects of antihistamines, we first should pay attention to the intercorrelation coefficients of these hpophilicity parameters (Table 2). From Table 2 it appears that ^;,Jk ...... is corre- lated with the Van der Waals volume Vw (r = 0.891). A similar correlation between /x,~k,,,,~ and molar volume (V~) also exists in the data of Van de Waterbeemd and Kansy (1992) (r = 0.744). As correlated parameters should not be used in multivariate analysis. Eq. 8 should be used for the prediction of brain penetration from /x.,,~ ...... and not Eq. 7. Table 2 also reveals that hydration capacity /x.,~k ..... is correlated with hydrogen-bond (donor) capacity A log P,,,.~ ,,tk (r = 0.683). If we leave out the most deviant outlier cicletanide (20). the correlation is increased to r = 0.821. A similar correlation can be found in the data of El Tayar et al. (1992) (n = 118. r = 0.923). These correla- uon data indicate that, although hydrauon capacity. /x.,,~ ...... . and hydrogen-bonding capacity. A log P. are defined differently, they largely de- scribe the same molecular properties, ~.e. those related to the hydrauon process. 3.4. Hydrogen bonding capacity (A log Poc~ .,~) and brain penetration 3.4. I. A log P of" sedating antihistamines According to the .,1 log P model of Young et al. (1988) (see also Eq. 6). one would expect low • -llogP,,c, .,~k values for the classical sedating antihistamines. In a theoretical study of El Tayar et al. (1991) in which JlogP,,c,.;,~ k is mainly related to H-bond donor capacity, 75 compounds were studied with zero, one or two hydrogen bond donor groups (e.g. -OH, -NH 2, etc.). The ..1 log P,~, .,l~ values were shown to range from -0.79 (n-pentane) to 4.65 (sulfathiazole). In correspondence w~th these data. most classical H ~-antagonists which lack an H-donor group such as ! to 4 and 7 have low A log P,,c~ ~k values in the range of 0.46-1.08. Compounds 2,4 and 7 which contain an extra hydrogen-bond acceptor group (an aromatic nitrogen) have slightly higher .llogP,,~, .,,k values than compounds 1 and 3 which lack such a function. Although azatadine (5) also contains an aromatic nitrogen atom and lacks H-donor groups, this compound has a relatively higher A log Po~.,_dl ~ value (1.77) when compared to the other more flexible compounds 2.4 and 7. The relatively high Alog P,,~, .,,~ of compound 6 (1.96) is explained by the presence of an additional hydroxyl group. On the whole, the ..1 log P,,,.~-,,k values (<2) of these sedating H~-antihistamines are of modest magnitude and are in line with the brain-penetra- uon model found by Young et al. Table 2 lntercorrelatlon matrix of hpophlhclty parameters presented in Table I log P .... log P,,.. -1 log P $\~ ^ .,,~ log D .... . log P, log P,,,,, 0 511 - A log P 0 221 0 724 Vw 0 660 0.379 ^ ,,ik II 428 0.084 log D ..... , 0 471 0.10(I 0 407 0 683 0 891 - 0 266 0 727 0.658
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`A M ter Laak et al / European Journal of Pharrnaceutwal Sctences 2 (1994) 373-384 381 3.4.2. A log P of non-sedating antihistamines Although it is found that sedating antihis- tamines have moderate AlogP values, the ,~ log Po~,-~k values of the non-sedating antihis- tamines (8-13) demonstrate that a moderate za log Po~-,tk value does not necessarily imply a high brain-penetration capacity. For example, compound 8 has only a marginally higher A log P,,c, ,,~k value (2.00) than its sedating coun- terpart 5 (A log Poet-ark = 1.77). Thus, the model of Young et al. (1988) cannot explain the low brain-penetration capacity of loratadine. Also the moderate A log P,,~.,_~k values of com- pounds 10, 11 and 12 (1.91, 2.61 and 1.75, respec- tively) do not fit the model of Young since the antihypertensive drug clonidine with a A log Po~,-,,tk value of 2.44 was reported to readily enter the brain (Young ct al., 1988). The moder- ate H-bond donor capacity of compounds 10-12 is due to the presence of nitrogen atoms in the guanidino group, while the remaining part of the molecules contains only H-bond acceptor groups. Terfenadine (13) has a relatively high A log P,,, ,tk value (3.06), due to the presence of two H-bond donating hydroxyl groups. But again, this value is not high enough to fit the A log P model of Young et al. (1988). Only cetirizinc (9) which has the highest A log Po~,-~,~k value (3.8