Hydrophobicity: the physical property of a molecule that is seemengly repelled from a mass of water. Lipophilicity (as an extension of the hydrophobic character): includes favorable interactions that contribute to the distribution of a chemical entity between water and other solubilizing media, representing a manifestation of the characteristics of the system in which the solute is placed. The measure of the hydrophobic character: log K o/w or simply, log P.
n-Octanol A O A O K O / W A W A W Water 1. If [A] o or [A] W are , very sensitive methods are necessary for assaying A. 2. Mutual relative solubility of the two media ( n -octanol in water and water in n -octanol, respectively). i.e. - solubility of n -octanol in water at 25 o C is 0.56 g/L.
A V S . Ph . M . Ph . K k k A A V M . Ph S . Ph . M.Ph. A W If k w is the retention factor for a hypothetical M.Ph. composition containing 0% Organic Modifier: C8 S. bulk Ph assimi A O lated . A to n - K k ; octan O / W W ol A A log K log P log k Log layer O / W W Si Si Si Si ... ... O O O O O O O . . . . . . . . . . . .
4.5 y = 0.0006x 2 - 0.0775x + 4.0487 4 R 2 = 0.9995 3.5 k w Morphologic modification of the apolar 3 Log (k') S.Ph. in water rich M.Ph. ? log k 2.5 2 1.5 1 y = -0.0283x + 2.1268 0.5 R 2 = 0.9987 0 0 10 20 30 40 50 60 70 (% of Organic Modifier) % Organic Solvent log P a log k bS c W S is the slope of the linear regression, a, b, c are characteristics of the S.Ph. K. Valko, V. Slegeli, J. Chromatogr. A, 631 (1993) 49-61.
6 y = 0.9687x + 0.1304 R 2 = 0.9831 5 Chromatographic Log P Model set of compounds Target 4 compound 3 2 1 0 0 1 2 3 4 5 6 Known Log P
O O O P O O P O + + N N O O O O O O O O O K IAM K M O modelled by Silica Membrane bilayer IAM column Predicting Intestinal Drug Permeability O O O O H N H N H N H N Si Si Si Si O O O O O O O O O O O O IAM.PC IAM.PC.DD2 C. Pidgeon, et al., J. Med. Chem., 38 (1995) 590-594.
The CHI scale : % (v) of ACN required to achieve an equal distribution of the compound between M.Ph. and S. Ph. Gradient elution conditions! log k W t f ( ) R S K. Valko, C. Bevan, D. Reynolds, Anal. Chem., 69 (1997) 2022-2029.
160.00 y = -411.11x + 140.45 R 2 = 0.9994 y = -93.271x + 35.956 140.00 2 = 0.9992 R y = -44.822x + 18.093 R 2 = 0.9991 120.00 MP y = -21.925x + 9.0938 EP R 2 = 0.9993 100.00 PP y = -10.715x + 4.5966 BP R 2 = 0.9988 PeP y = -5.045x + 2.3482 80.00 k HP R 2 = 0.9969 OP y = -2.2946x + 1.2665 R 2 = 0.9928 60.00 40.00 20.00 0.00 0 0.05 0.1 0.15 0.2 0.25 (V inj /V 0 ) C. Sarbu, R.D. Nascu-Briciu, D. Casoni, A. Kot-Wasik, J. Namiesnik, J. Chromatogr. A, 1266 (2012) 536-544.
Log(BB) [-2 1] (1) A Brain ( ) Log BB Favorable distribution: Log(BB) > 0.3; A Poor Distribution: Log(BB) < -1; Blood SS Log(BB) = f ( molecular mass – Mw; hydrophobic character – log P; polar surface area – PSA; n o . of rotatable bonds; n o . of H-bond donors; n o . of H-bond acceptors; 3D-molecular field descriptors; electropological state indices; critical micelle concentration – CMC D ; cross sectional area – A D ; permeability coefficient – PC; polarizability – CMR … and others ) Successful CNS Drug (2) Descriptor Condition Descriptor Condition Molecular weight Mw < 450 Water solubility S > 60 g/mL Hydrophobic character Log P < 5 Metabolic stability > 80% after 1 h No. of H-bond donor P450 enzyme CIP inhibition 3 < 50% at 30 M No. of H-bond acceptor < 7 Metabolization by CYP2D6 Not significant No. of rotatable bonds < 8 CYP3A4 inducer No potent PSA < 60 70 Å 2 Polar surface area P-glycoprotein substrate No H-bonds <8 Affinity to serum albumin K D < 10 M > 1 10 -6 cm/sec Acid character pK a [7.5 10.5] Effective permeability (1) M.H. Abraham et al., J. Pharm.Sci., 86 (1992) 310-315. H. Pajouhesh, G.R. Lenz, NeuroRx , 2 (2005) 541-553. (2)
Inhibited Enzyme Enzyme AChE AChE O (S) O (S) + Ser OH Ser R 1 O or X P R3 O P R3 - R 1 OH or HX (X = F, CN) O(S)R 2 O(S)R 2 Oximate AChE AChE O (S) - H O -H + O - + Ser O P R3 Ser O N N N + N + + H + O(S)R 2 Quaternary Reactivated Ammonium Enzyme Oxime + O (S) R 2 (S)O P R3 O N N + Oxime - Inhibitor Complex V. Voicu, F.S. Radulescu, A. Medvedovici, EOMT, 9 (2013) 31-50.
Aged inhibited Enzyme Time of E PO - ageing Minimum extent of Intrinsic reactivation Ageing toxicity granting survival Access to the Structural diversity Access to the inhibited site Biodistribution Biodistribution esteratic site Phosphylated OP inhibited Active Complex Oxime Enzyme Enzyme Reactivation Intoxication + + + P E P E P O E P O O E OP agent Oxime Half life AChE Spontaneous re-inactivation Detoxication Reactivation Intrinsic Structural rate toxicity diversity POH + + E P O POH
+ N N N N + N OH N O I OH Br Pralidoxime ( PAM ) N 2-[(hydroxyimino)methyl]-1-methylpyridin-1-ium 2-(Hydroxyimino-methyl)-1,3 -dimethyl-3H-imidazol-1-ium (1) O NH 2 RP (C8) + + + N O N N O + N N O Cl I I Cl IP (C8) H O OH N ( HI-6 ) N 2,1-(2-hydroxyiminomethylpyridinium)-3- 1-Methyl-3-(3-oxo-1-aza-bicyclo[2.2.2]octane RP (PFP) (4-carbamoylpyridinium)-2-oxapropane -1-ylmethoxymethyl)-1H-imidazole- 2-carbaldehyde oxime (2) N N HILIC O + + OH N O N OH + N O + N N N O Cl ZIC-HILIC Cl I I Obidoxime ( LuH-6 ) OH 1,3-bis(4-hydroxyiminomethylpyridinium) N AGP -2-oxapropane Dimethyl-carbamic acid 1-[2-(hydroxyimino-methyl) -3-methyl-3H-imidazol-1-ylmethoxymethyl]-1-aza- O bicyclo[2.2.2]octane-3-yl ester (3) Elution at 37 o C, N NH 2 Br + + N O OH N O N + N with 0.9% NaCl in the aqueous 2- O (CH 3 ) 2 SO 3 H O N component of the M.Ph. ( HLo-7 ) Pyridostigmine ( PRDS ) 1-(4-aminocarbonylpyridinio)methoxymethyl- Dimethyl-carbamic acid 1-methyl- 2,4-bis(hydroxyiminomethyl)pyridinium pyridin-3-yl ester V. Voicu, I. Sora, C. Sarbu, V. David, A. Medvedovici, J. Pharm. Biomed. Anal., 52 (2010) 508-516.
ALOGP AB/Log r xy WIN AClog P miLogP ALOGP MLOGP XLOGP2 XLOGP3 K OW s P -0.3203 0.4506 0.0480 0.5710 0.6181 0.2848 0.4872 0.5613 0.0980 C8 -0.4376 0.0837 -0.3339 0.2506 0.5477 0.5174 0.5099 0.1954 0.3173 IP/C8 -0.4263 0.2218 0.1311 0.6207 0.2632 0.5730 0.4450 0.5120 PFP 0.9014 log k w 0.0245 -0.6368 -0.7299 -0.5416 0.1208 -0.3697 -0.0949 ZIC- HILIC -0.8452 -0.9185 0.2229 -0.6872 -0.3437 -0.7154 -0.7032 -0.1652 -0.5616 -0.2121 HILIC -0.8085 -0.1513 -0.6918 -0.5747 -0.4001 0.2369 -0.2458 0.1005 AGP -0.8519 -0.8630 Extrapolation to = 0% Organic Modifier; Extrapolation to = 100% Organic Modifier Hydrophobicity descriptors resulting from the chromatographic retention behaviour are poorly correlated to log P values resulting from different computational algorithms.
r xy C8 IP/C8 PFP HILIC ZIC-HILIC AGP 0.7311 0.6180 -0.6758 -0.6010 C8 1.0000 -0.9064 0.5259 -0.1822 -0.5995 -0.0424 IP/C8 1.0000 -0.5340 -0.6967 -0.3789 PFP 1.0000 HILIC 1.0000 0.8819 0.9487 0.8086 ZIC-HILIC 1.0000 AGP 1.0000 1.5 y = -1.6602x - 0.1498 1 1 R 2 = 0.8215 3 0.5 LuH-6 HI-6 PRDS 0 2 HLo-7 ZIC-HILIC descriptor -0.5 -1 -1.5 -2 -2.5 -3 -3.5 PAM -4 -1 -0.5 0 0.5 1 1.5 2 RP descriptor
Position of Substituent (R) Substituent (R) # the oxime Acronym(s) Name Formula moiety 1 Ethyl -C 2 H 5 2, 3, 4 2-PAE, 3-PAE, 4-PAE 2 Butyl -C 4 H 9 2, 3 2-PAB, 3-PAB 3 Hexyl -C 6 H 13 2, 3, 4 2-PAH, 3-PAH, 4-PAH OH 4 Octyl -C 8 H 17 2, 3, 4 2-PAO, 3-PAO, 4-PAO N 5 Decyl -C 10 H 21 2, 3 2-PAD, 3-PAD 6 Dodecyl (Lauryl) -C 12 H 25 2, 3, 4 2-PAL, 3-PAL, 4-PAL + 7 Benzyl -CH 2 -C 6 H 5 2, 3, 4 2-PABn, 3-PABn, 4-PABn N 8 Ethyl-phenyl -(CH 2 ) 2 -C 6 H 5 2, 3, 4 2-PAPE, 3-PAPE, 4-PAPE R 9 Propyl-phenyl -(CH 2 ) 3 -C 6 H 5 3 3-PAPP 10 Butyl-phenyl -(CH 2 ) 4 -C 6 H 5 3, 4 3-PAPB, 4-PAPB 11 4-Methylbenzyl -CH 2 -C 6 H 4 -CH 3 2, 3, 4 2-PAMB, 3-PAMB, 4-PAMB -CH 2 -C 6 H 4 - 12 4- t -Butylbenzyl 3, 4 3-PATB, 4-PATB C(CH 3 ) 3 H. Ohta, T. Ohmori, S. Suzuki, H. Ykegaya, K. Sakurada, T. Takatori, Pharm. Res., 23 (2006) 2827-2833.
H O Stationary Phase H O O H H O H H O H O H Mobile Phase Alkyl Layer Aqueous Layer A Aqueous L. Si A M.Ph. O O O A Alkyl L.
25.00 bin k W + N N H O 20.00 lin k w 15.00 HYL k 10.00 k min 5.00 ISOELUT 0.00 0.00 20.00 40.00 60.00 80.00 100.00 k ( f ) (%ACN)
3.1000 bin log k W H O 2.9000 N 2.7000 + N 2.5000 2.3000 2.1000 1.9000 log k 1.7000 lin log k w 1.5000 LOGHYL 1.3000 1.1000 0.9000 log k min 0.7000 LOGISOELUT 0.5000 0.0 10.0 20.0 30.0 40.0 50.0 60.0 70.0 80.0 90.0 100.0 k log f ( ) (% ACN)
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