SLIDE 1
Hydrophobicity: the physical property of a molecule that is - - PowerPoint PPT Presentation
Hydrophobicity: the physical property of a molecule that is - - PowerPoint PPT Presentation
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
SLIDE 2
SLIDE 3
Water n-Octanol
AW AO
W O W O
A A K
/
- 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
- f n-octanol in water at 25 oC is 0.56 g/L.
SLIDE 4
Si O Si O Si O Si O O O O
.
.
. .
.
. .
.
. .
.
. ... ... M.Ph. S. Ph .
C8 bulk assimi lated to n-
- ctan
- l
layer
AO AW
k V V k A A K
Ph S Ph M Ph M Ph S A . . . . . . .
If kw is the retention factor for a hypothetical M.Ph. composition containing 0% Organic Modifier:
Log k P K k K
W A A W O W A W O
log log log ;
/ /
SLIDE 5
y = -0.0283x + 2.1268 R2 = 0.9987 y = 0.0006x2 - 0.0775x + 4.0487 R2 = 0.9995 0.5 1 1.5 2 2.5 3 3.5 4 4.5 10 20 30 40 50 60 70
% Organic Solvent Log (k')
kw
log k
(% of Organic Modifier)
c bS k a P
W
log log
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.
Morphologic modification of the apolar S.Ph. in water rich M.Ph. ?
SLIDE 6
y = 0.9687x + 0.1304 R2 = 0.9831 1 2 3 4 5 6 1 2 3 4 5 6
Known Log P Chromatographic Log P
Model set of compounds Target compound
SLIDE 7
- C. Pidgeon, et al., J. Med. Chem., 38 (1995) 590-594.
O Si O O N H O O Si O O N H O O O O P O O O N
+
O O Si O O N H O O O P O O O N
+
O O O Si O O N H O O O
IAM.PC IAM.PC.DD2
Silica Membrane bilayer IAM column
KM KIAM
modelled by
Predicting Intestinal Drug Permeability
SLIDE 8
- K. Valko, C. Bevan, D. Reynolds, Anal. Chem., 69 (1997) 2022-2029.
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 ( S k f t
W R
SLIDE 9
y = -411.11x + 140.45 R2 = 0.9994 y = -93.271x + 35.956 R
2 = 0.9992
y = -44.822x + 18.093 R2 = 0.9991 y = -21.925x + 9.0938 R2 = 0.9993 y = -10.715x + 4.5966 R2 = 0.9988 y = -5.045x + 2.3482 R2 = 0.9969 y = -2.2946x + 1.2665 R2 = 0.9928
0.00 20.00 40.00 60.00 80.00 100.00 120.00 140.00 160.00 0.05 0.1 0.15 0.2 0.25
(Vinj/V0)
k
MP EP PP BP PeP HP OP
- C. Sarbu, R.D. Nascu-Briciu, D. Casoni, A. Kot-Wasik, J. Namiesnik, J.
- Chromatogr. A, 1266 (2012) 536-544.
SLIDE 10
SS Blood Brain
A A BB Log ) (
Log(BB) [-2 1] (1) Favorable distribution: Log(BB) > 0.3; Poor Distribution: Log(BB) < -1;
(1) M.H. Abraham et al., J. Pharm.Sci., 86 (1992) 310-315. (2)
- H. Pajouhesh, G.R. Lenz, NeuroRx, 2 (2005) 541-553.
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
3 P450 enzyme CIP inhibition < 50% at 30 M
- No. of H-bond acceptor
< 7 Metabolization by CYP2D6 Not significant
- No. of rotatable bonds
< 8 CYP3A4 inducer No potent Polar surface area PSA < 6070 Å2 P-glycoprotein substrate No H-bonds <8 Affinity to serum albumin KD < 10 M Acid character pKa [7.510.5] Effective permeability > 1 10-6 cm/sec
Log(BB) = f (molecular mass – Mw; hydrophobic character – log P; polar surface area – PSA; no. of rotatable bonds; no. of H-bond donors; no. of H-bond acceptors; 3D-molecular field descriptors; electropological state indices; critical micelle concentration – CMCD; cross sectional area – AD; permeability coefficient – PC; polarizability – CMR … and others)
SLIDE 11
OH P O (S) R1O or X O(S)R2 R3
AChE
O
AChE
N O H N O N O P R2(S)O R3 O (S) O P O (S) R3 O(S)R2
AChE
O P O (S) R3 O(S)R2
AChE
Ser
+
- R1OH or HX (X = F, CN)
Ser
- + H+
- H+
- +
Ser N+ N+ N+
+
Enzyme Inhibited Enzyme Quaternary Ammonium Oxime Oximate Reactivated Enzyme Oxime - Inhibitor Complex Ser
- V. Voicu, F.S. Radulescu, A. Medvedovici, EOMT, 9 (2013) 31-50.
SLIDE 12
P E O
POH Enzyme
Detoxication
P E
+
E E
+
P
PO-
+
O P E O E
+
P O
+
POH
Intoxication Spontaneous Reactivation Ageing Reactivation
OP agent OP inhibited Enzyme Oxime Active Complex Phosphylated Oxime Aged inhibited Enzyme
Biodistribution Access to the esteratic site Biodistribution Intrinsic toxicity Access to the inhibited site Structural diversity Structural diversity Intrinsic toxicity Half life Time of ageing AChE re-inactivation rate Minimum extent of reactivation granting survival
SLIDE 13
RP (C8) IP (C8) RP (PFP) HILIC ZIC-HILIC AGP
Elution at 37 oC, with 0.9% NaCl in the aqueous component of the M.Ph.
N
+
N OH N N O Br N
+
N
+
O N O H NH2 O Cl Cl N
+
N
+
O N OH N OH Cl Cl N
+
N
+
O N O H N OH NH2 O (CH3)2SO3
2-
Pralidoxime (PAM) 2-[(hydroxyimino)methyl]-1-methylpyridin-1-ium (HI-6) 2,1-(2-hydroxyiminomethylpyridinium)-3- (4-carbamoylpyridinium)-2-oxapropane Obidoxime (LuH-6) 1,3-bis(4-hydroxyiminomethylpyridinium)
- 2-oxapropane
(HLo-7) 1-(4-aminocarbonylpyridinio)methoxymethyl- 2,4-bis(hydroxyiminomethyl)pyridinium N
+
N N OH I N
+
O O N
+
N N OH I I N
+
O N O O N
+
N N OH I I N
+
O O N Br 2-(Hydroxyimino-methyl)-1,3
- dimethyl-3H-imidazol-1-ium (1)
1-Methyl-3-(3-oxo-1-aza-bicyclo[2.2.2]octane
- 1-ylmethoxymethyl)-1H-imidazole-
2-carbaldehyde oxime (2) Dimethyl-carbamic acid 1-[2-(hydroxyimino-methyl)
- 3-methyl-3H-imidazol-1-ylmethoxymethyl]-1-aza-
bicyclo[2.2.2]octane-3-yl ester (3) Pyridostigmine (PRDS) Dimethyl-carbamic acid 1-methyl- pyridin-3-yl ester
- V. Voicu, I. Sora, C. Sarbu, V. David, A. Medvedovici, J. Pharm. Biomed. Anal., 52 (2010) 508-516.
SLIDE 14
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.
0.1005
- 0.8630
- 0.2458
0.2369
- 0.4001
- 0.5747
- 0.6918
- 0.8519
- 0.1513
AGP
- 0.2121
- 0.8085
- 0.5616
- 0.1652
- 0.7032
- 0.7154
- 0.3437
- 0.6872
0.2229 HILIC
- 0.0949
- 0.9185
- 0.3697
0.1208
- 0.5416
- 0.7299
- 0.6368
- 0.8452
0.0245 ZIC- HILIC 0.5120 0.4450 0.5730 0.2632 0.6207 0.9014 0.1311 0.2218
- 0.4263
PFP 0.3173 0.1954 0.5099 0.5174 0.5477 0.2506
- 0.3339
0.0837
- 0.4376
IP/C8 0.0980 0.5613 0.4872 0.2848 0.6181 0.5710 0.0480 0.4506
- 0.3203
C8
log kw
KOW
WIN
XLOGP3 XLOGP2 MLOGP ALOGP miLogP AB/Log P AClog P ALOGP s
rxy
SLIDE 15
y = -1.6602x - 0.1498 R2 = 0.8215
- 4
- 3.5
- 3
- 2.5
- 2
- 1.5
- 1
- 0.5
0.5 1 1.5
- 1
- 0.5
0.5 1 1.5 2 RP descriptor ZIC-HILIC descriptor
PAM PRDS HI-6 3 HLo-7 2 LuH-6 1
rxy C8 IP/C8 PFP HILIC ZIC-HILIC AGP C8 1.0000 0.7311 0.6180
- 0.6758
- 0.9064
- 0.6010
IP/C8 1.0000 0.5259
- 0.1822
- 0.5995
- 0.0424
PFP 1.0000
- 0.5340
- 0.6967
- 0.3789
HILIC 1.0000 0.8819 0.9487 ZIC-HILIC 1.0000 0.8086 AGP 1.0000
SLIDE 16
- H. Ohta, T. Ohmori, S. Suzuki, H. Ykegaya, K. Sakurada, T. Takatori, Pharm. Res., 23 (2006) 2827-2833.
N
+
R OH N
# Substituent (R) Name Substituent (R) Formula Position of the oxime moiety Acronym(s) 1 Ethyl
- C2H5
2, 3, 4 2-PAE, 3-PAE, 4-PAE 2 Butyl
- C4H9
2, 3 2-PAB, 3-PAB 3 Hexyl
- C6H13
2, 3, 4 2-PAH, 3-PAH, 4-PAH 4 Octyl
- C8H17
2, 3, 4 2-PAO, 3-PAO, 4-PAO 5 Decyl
- C10H21
2, 3 2-PAD, 3-PAD 6 Dodecyl (Lauryl)
- C12H25
2, 3, 4 2-PAL, 3-PAL, 4-PAL 7 Benzyl
- CH2-C6H5
2, 3, 4 2-PABn, 3-PABn, 4-PABn 8 Ethyl-phenyl
- (CH2)2-C6H5
2, 3, 4 2-PAPE, 3-PAPE, 4-PAPE 9 Propyl-phenyl
- (CH2)3-C6H5
3 3-PAPP 10 Butyl-phenyl
- (CH2)4-C6H5
3, 4 3-PAPB, 4-PAPB 11 4-Methylbenzyl
- CH2-C6H4-CH3
2, 3, 4 2-PAMB, 3-PAMB, 4-PAMB 12 4-t-Butylbenzyl
- CH2-C6H4-
C(CH3)3 3, 4 3-PATB, 4-PATB
SLIDE 17
O Si O O O H O H O H H O O H H O H H Mobile Phase Stationary Phase Alkyl Layer Aqueous Layer
AM.Ph. AAlkyl L. AAqueous L.
SLIDE 18
0.00 5.00 10.00 15.00 20.00 25.00 0.00 20.00 40.00 60.00 80.00 100.00
(%ACN) k
ISOELUT kmin kW
bin
kw
lin
HYL
) ( f k
N
+
N O H
SLIDE 19
0.5000 0.7000 0.9000 1.1000 1.3000 1.5000 1.7000 1.9000 2.1000 2.3000 2.5000 2.7000 2.9000 3.1000 0.0 10.0 20.0 30.0 40.0 50.0 60.0 70.0 80.0 90.0 100.0
(% ACN) log k
log kmin LOGISOELUT
) ( log f k
log kW
bin
log kw
lin
LOGHYL N
+
N O H
SLIDE 20
N
+
N O H
y = 0.0097x2 - 1.1351x + 36.865 R2 = 0.9321 0.00 5.00 10.00 15.00 20.00 25.00 30.00 35.00 10 20 30 40 50 60 70 80 90 100
(%ACN) k
a b ISOELUT 2
y = -1.05744 x + 38.96723 R2 = 0.9497 y = 0.32577 x - 17.5287 R2 = 0.9344
) ( ) ( 1
2 1 1 2
b b a a ISOELUT
y = 413.9 x -1.1072 R2 = 0.9730 y = 2E-05 x 2.9679 R2 = 0.9579 ) ( 1 ( 1 2
2 1
) ( 2
b b
a a ISOELUT
SLIDE 21
min 2 4 6 8 10 12 14 16 18 50 3-PAE-I (30% Solv. B) 3- PAB-BR (50% Solv. B) 3-PAH-BR (70% Solv. B) 3-PAO-BR (70% Solv. B) 3-PAD-BR (70% Solv. B) 3-PAL-BR (70% Solv. B)
SLIDE 22
3-PABN-BR (50% Solv. B) 3-PAPE-BR (60% Solv. B) 3-PAPP-BR (60% Solv. B) 3-PAMB-BR (60% Solv. B) 3-PATB-BR (70% Solv. B) 3-PAPB-BR (70% Solv. B) min 2 4 6 8 10 12 14 16 18 50
SLIDE 23
- V. Voicu, C. Sarbu, F. Tache, F. Micale, S.F. Radulescu, K. Sakurada, H. Ohta, A. Medvedovici, Talanta, 122 (2014) 172-179.
Correlation Coefficients Correlated sets
ALOGPs AC logP miLogP KOWWIN XLOGP2 XLOGP3 Hy MLOGP ALOGP LogD7 SlogD7.4
kmin 0.958 0.977 0.934 0.963 0.977 0.983 -0.758 0.935 0.943 0.884 0.969 log kmin 0.938 0.977 0.927 0.973 0.964 0.978 -0.849 0.954 0.944 0.918 0.969 ISOELUT 0.842 0.915 0.835 0.942 0.895 0.899 -0.891 0.914 0.904 0.931 0.902 LOG ISOELUT 0.809 0.881 0.810 0.904 0.865 0.873 -0.874 0.880 0.855 0.894 0.864 ISOELUT 1 0.479 0.512 0.460 0.508 0.484 0.529 -0.518 0.577 0.393 0.537 0.503 LOG ISOELUT 1 0.678 0.740 0.661 0.752 0.700 0.750 -0.817 0.806 0.640 0.788 0.738 ISOELUT 2 0.552 0.598 0.526 0.602 0.558 0.621 -0.730 0.668 0.493 0.642 0.609 LOG ISOELUT2 0.193 0.209 0.117 0.214 0.201 0.226 -0.267 0.240 0.135 0.232 0.227 kw
lin
0.788 0.784 0.767 0.753 0.793 0.787 -0.546 0.803 0.770 0.652 0.770 log kw
lin
0.847 0.862 0.836 0.843 0.862 0.863 -0.672 0.878 0.840 0.766 0.845 kw
bin
0.754 0.812 0.756 0.787 0.817 0.800 -0.570 0.814 0.778 0.714 0.771 log kw
bin
0.139 0.278 0.202 0.304 0.246 0.239 -0.377 0.257 0.259 0.374 0.230 HYL 0.488 0.472 0.479 0.413 0.458 0.502 -0.327 0.520 0.363 0.363 0.464 LOG HYL 0.430 0.405 0.420 0.346 0.400 0.440 -0.245 0.464 0.298 0.291 0.396
SLIDE 24
Mw - molecular mass; Mol. Vol. - Molecular Volume: Diff. Coeff. – molecular diffusion coefficient in water; Peff – human jejunal effective permeability; log MDCK – apparent MDCK COS permeability; Pcornea – permeability through rabbit cornea; log(FaSSGF) – solubility in fasted state simulated gastric fluid, log(FaSSIF) – solubility in fasted state simulated intestinal fluid, log(FeSSIF) – solubility in fed state simulated intestinal fluid; Log BBB - the logarithm of the brain/blood barrier; PrUnbnd – the percent unbound to blood plasma proteins; Vd – the pharmacokinetic volume of distribution in humans; by ADMET Predictor, vers. 5.0.0012, Simulation Plus Inc. (U.S.A)
Descriptors Mw Mol.Vol.
- Diff. Coef.
Peff Log (MDCK COS) Pcornea Log (Sw) Log (FaSSGF) Log (FaSSIF) Log (FeSSIF) LogBBB PrUnbnd Vd kmin 0.861 0.946 -0.887 0.711 -0.764 0.304
- 0.899 -0.969
- 0.859
- 0.894
0.852 -0.416 0.889 log kmin 0.909 0.967 -0.953 0.726 -0.728 0.401
- 0.939 -0.966
- 0.924
- 0.932
0.792 -0.539 0.884 ISOELUT 0.929 0.950 -0.971 0.776 -0.707 0.512
- 0.941 -0.923
- 0.931
- 0.949
0.648 -0.629 0.849 LOG ISOELUT 0.894 0.914 -0.947 0.729 -0.633 0.486
- 0.900 -0.884
- 0.905
- 0.905
0.647 -0.622 0.836 kw
lin
0.600 0.720 -0.717 0.438 -0.687 0.105
- 0.661 -0.736
- 0.673
- 0.708
0.754 -0.205 0.629 log kw
lin
0.724 0.820 -0.822 0.544 -0.709 0.217
- 0.774 -0.827
- 0.777
- 0.809
0.768 -0.339 0.732
SLIDE 25
0.00 2.00 4.00 6.00 8.00 10.00 12.00 14.00 10 20 30 40 50 60 70 80 90 100
%ACN k
20 oC 25oC 30oC 35 oC 40 oC 45 oC
HI RP HI RP
G G k k
N
+
N O H
SLIDE 26
y = 1052.5x - 1.6106 R2 = 0.9901 y = 912.46x - 1.7217 R2 = 0.9879 y = 858.23x - 1.4567 R2 = 0.9916 y = 526.73x + 0.0398 R2 = 0.9952 y = 181.54x + 1.9394 R2 = 0.9986 0.00 0.50 1.00 1.50 2.00 2.50 3.00 0.0031 0.00315 0.0032 0.00325 0.0033 0.00335 0.0034 0.00345
1/T ln k
10% ACN 40% ACN 55% ACN 80% ACN 90% ACN
) (
/ /
71828 . 2 ) ( ) ( ); ln ( ); ln ( ) ln ( ; ln ; ln ; ; 1 ln ; 1 ln ; ;
T RP HILIC A T RP HILIC B
e RP FS HILIC FS HILIC RP RP HILIC HILIC RP HILIC RP FM HILIC FS HILIC HILIC FM RP FS RP RP FM FS HILIC HILIC RP RP HILIC HILIC HILIC RP RP RP HILIC HILIC RP RP RP RP
V V S S T B B R S S T H H V V A R S V V A R S V V A R S A R S A R S B R H B R H A T B k A T B k S T H G S T H G
K mol KJ H K mol KJ H
HILIC RP
/ 38 . 4 / 75 . 8
K mol J S K mol J S
HILIC RP
/ 93 . 19 / 38 . 6
HILIC Ph S RP Ph S
V V
. . . .
SLIDE 27
PCA on covariance matrices k/log k and computed descriptors
- 1.0
- 0.8
- 0.6
- 0.4
- 0.2
0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 PC1 / log k
- 0.6
- 0.4
- 0.2
0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4
2-PAE 4-PAE 3-PAE 2-PAB 3-PAB 2-PAH 3-PAH 4-PAH 2-PAO 3-PAD 2-PAD 4-PAO 3-PAO 2-PAL 3-PAL 4-PAL 3-PAPE 4-PAPE 2-PAMB 4-PABn 3-PABn 3-PAMB 4-PAMB 3-PATB 4-PATB 2-PABn 3-PAPP 3-PAPB 4-PAPB 2-PAPE
P C2 / log k
SLIDE 28
Loadings representation after applying PCA on matrices formed by calculated log P and hydrophobicity indices.
- 1.0
- 0.5
- 1.0
0.0 0.5 1.0
- 0.5
0.0 0.5 1.0 PC1 : 68.82% PC2 : 12.77%
PC1/log k ISOELUT kmin log kmin ISOELUT 1 LOG HYL HYL ISOELUT 2 LOG ISOELUT 2 LOG ISOELUT 1 PC1/k log kw
bin
LOG ISOELUT kw
bin
kw
lin
log kw
lin
Hy Computed log P
SLIDE 29
0.00 0.50 1.00 1.50 2.00 2.50 3.00 10 20 30 40 50 60 70 80 90 100
(%ACN) k
0.00 5.00 10.00 15.00 20.00 25.00 10 20 30 40 50 60 70 80 90 100
(%ACN) k
N H S O H O H NH2 O OH
log P (s/f method) = -2.39 log P (s/f method) = 4.15 L- DOPA Phenothiazine
SLIDE 30
- 1. Other chromatographic retention mechanisms than RP may
successfully produce indices for lipophilicity scales.
- 2. For the bimodal RP+HILIC retention behaviour, kmin, ISOELUT,
log kmin, LOGISOLEUT closely correlate with computed log P.
- 3. Such approaches work better within compound classes.
y = 1.1892x + 3.5108 rxy= 0.9631 2 4 6 8 10 12
- 2.00
- 1.00
0.00 1.00 2.00 3.00 4.00 5.00
Log P (KOW WIN) k min
SLIDE 31
Things you'll meet, of many a kind, Things you'll meet, of many a kind, Sights and sounds, and tales, no end, Sights and sounds, and tales, no end, But to keep them all in mind, But to keep them all in mind, Who would bother to attend? Who would bother to attend? Very little does it matter Very little does it matter If you can yourself fulfil, If you can yourself fulfil, That, with idle em That, with idle empty chatter, pty chatter, Days go past and days come still. Days go past and days come still.
- M. Eminescu, Glossa
- M. Eminescu, Glossa