pkas
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Chemistry & Biology 14 Supplemental Data Examination of the Role of Intestinal Fatty Acid-Binding Protein in Drug Absorption Using a Parallel Artificial Membrane Permeability Assay Tony Velkov, James Horne, Aisha Laguerre, Eric Jones, Martin J. Scanlon, and Christopher J.H. Porter FENAMATES H N O OH Cl CH3 H N O HO CF3 H N O Cl OH Cl CH3 H N O HO CH3 CH3 H N Cl Cl O HO Tolfenamic Acid Flufenamic Acid Meclofenamic Acid Mefenamic Acid Diclofenac K i =2.8 ± 0.7 µM K i = 3.7 ± 0.8µM K i =8.9 ± 2.0 µM K i = 62.8±10.2 µM K i =152.7 ±9.6 µM logP=5.9; pKa=3.7 logP=5.6; pKa=3.7 logP=5.9; pKa=4.2 logP=5.3; pKa=3.7 logP=3.3; pKa=4.2 logD(7.4)=2.3 logD(7.4)=2.0 logD(7.4)=2.3 logD(7.4)=1.8 logD(7.4)=0.1 PROPIONIC ACID DERIVATIVES O O OH CH3 O F OH CH3 O O OH CH3 O OH O CH3 CH3 Fenoprofen Flurbiprofen Ketoprofen Naproxen K i =14.2 ± 0.5µM K i = 15.4±2.8 µM K i =23.7 ±3.0 µM K i =56.1 ±4.2 µM logP=3.8; pKa=4.5 logP=4.1; pKa=4.3 logP=2.8; pKa=4.6 logP=3.0; pKa=4.2 logD(7.4)=0.7 logD(7.4)= 0.9 logD(7.4)=-0.3 logD(7.4)=0.03 O O CH3 CH3 O OH CH3 CH3 CH3 N O O OH CH3 Nabumetone Ibuprofen Indoprofen K i =NB K i = 32.2±4.2 µM K i = 129.1±1.8 µM logP=2.8; pKa=NI logP=3.7; pKa=4.4 logP=1.7; pKa=4.4 logD(7.4)=2.8 logD(7.4)=0.8 logD(7.4)=-1.2
description
Different pas of various drugs.
Transcript of pkas
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Chemistry & Biology 14
Supplemental Data
Examination of the Role of Intestinal Fatty
Acid-Binding Protein in Drug Absorption Using
a Parallel Artificial Membrane Permeability Assay Tony Velkov, James Horne, Aisha Laguerre, Eric Jones, Martin J. Scanlon, and Christopher J.H. Porter
FENAMATES
HN
O OH
Cl
CH3
HN
OHO
CF3
HN
OCl
OH
Cl
CH3
HN
OHOCH3
CH3
HN
Cl
Cl
O
HO
Tolfenamic Acid Flufenamic Acid Meclofenamic Acid Mefenamic Acid Diclofenac Ki=2.8 0.7 M Ki= 3.7 0.8M Ki=8.9 2.0 M Ki= 62.810.2 M Ki=152.7 9.6 M logP=5.9; pKa=3.7 logP=5.6; pKa=3.7 logP=5.9; pKa=4.2 logP=5.3; pKa=3.7 logP=3.3; pKa=4.2 logD(7.4)=2.3 logD(7.4)=2.0 logD(7.4)=2.3 logD(7.4)=1.8 logD(7.4)=0.1
PROPIONIC ACID DERIVATIVES
O
O OH
CH3
O
F
OH
CH3
O
O
OH
CH3
O OH
O
CH3
CH3 Fenoprofen Flurbiprofen Ketoprofen Naproxen Ki=14.2 0.5M Ki= 15.42.8 M Ki=23.7 3.0 M Ki=56.1 4.2 M logP=3.8; pKa=4.5 logP=4.1; pKa=4.3 logP=2.8; pKa=4.6 logP=3.0; pKa=4.2 logD(7.4)=0.7 logD(7.4)= 0.9 logD(7.4)=-0.3 logD(7.4)=0.03
O
O
CH3
CH3
O
OH
CH3
CH3
CH3
N
O
O
OH
CH3
Nabumetone Ibuprofen Indoprofen Ki=NB Ki= 32.24.2 M Ki= 129.11.8 M logP=2.8; pKa=NI logP=3.7; pKa=4.4 logP=1.7; pKa=4.4 logD(7.4)=2.8 logD(7.4)=0.8 logD(7.4)=-1.2
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FIBRATES
O
OH
O
O
ClCH3
CH3
O
ClCl
O
OHCH3
CH3
OOO
HN OH
Cl
CH3
CH3 Fenofibric Acid Ciprofibrate Bezafibrate Ki= 1.00.2 M Ki=23.5 1.1 M Ki=32.9 0.7 M logP=3.9; pKa=3.1 logP=2.5; pKa=3.3 logP=3.6; pKa=3.3 logD(7.4)=-0.04 logD(7.4)=-1.3 logD(7.4)=-0.2
O
O
OH
ClCH3
CH3
Clofibric Acid Ki=51.5 1.8 M logP=2.7; pKa=3.2 logD(7.4)=-1.1 NAPHTHALENE DERIVATIVES
HN
-O3S
NH
SO3-
NH OSO3H
SO3-
NH
H3C
bisANS ANS TNS Ki=2.00.5 M Ki= 3.20.3 M Ki= 45.010.1 M logP=5.8; pKa=1.7 logP=?; pKa=1.4 logP=3.3; pKa=1.0 logD(7.4)=-2.2 logD(7.4)=-1.3 logD(7.4)=-0.8
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BRIDGED BI-PHENYL DERIVATIVES
N
N
O
O
O
O
CH3
CH3
CH3
CH3
CH3
CH3
CH3
N N
N
O
CH3 CH3
CH3
HN
NH
O
O Verapamil Pyrilamine Phenytoin Ki=NB Ki=NB Ki= NB logP=5.0; pKa=8.9 logP=3.3; pKa=9.0 logP=2.92; pKa=8.3 logD(7.4)=3.4 logD(7.4)=1.6 logD(7.4)=2.47
O
Cl
Cl
OO
CH3
N+
O
OH
OH
O
O
CH3
C
O
N
O
CH3
CH3H
Bifenox Benzyl salicylate Mepronil Ki=NB Ki= NB Ki=NB logP=5.8; pKa=NI logP=4.0; pKa=8.1 logP=4.1; pKa=13.1 logD(7.4)=5.8 logD(7.4)=3.9 logD(7.4)=4.1
NH
H3C CH3 N-Phenyl-2,3-xylidine Ki=NB logP=3.9; pKa=0.8 logD(7.4)=3.9 OTHER MONO-CARBOXYLIC ACID DERIVATIVES
O
OH
O
Cl
F
F
F
NO2
OO
OH
O
OH Acifluorfen 2-Naphthoxyacetic acid 1-Naphthaleneacetic acid Ki= 4.21.2 M Ki=7.2 1.9 M Ki=32.1 5.7 M logP=5.9; pKa=1.9 logP=2.6; pKa=3.2 logP=2.7; pKa=4.3 logD(7.4)=1.9 logD(7.4)=-1.3 logD(7.4)=-0.3
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COH
O OH
H
CH2
H
O
O
OH
O OH
CH3CH3 Benzilic Acid Jasmonic Acid Valproate Ki= 110.813.9 M Ki= 140.120.8M Ki=242.723.1 M logP=3.0; pKa= 3.0 logP=1.7; pKa=4.5 logP=2.8; pKa=5.0 logD(7.4)=-1.1 logD(7.4)=-1.2 logD(7.4)=0.2
O
O
O
OH
CH3
NN
O
O
OH
CH3
CH3
Asprin Nalidixic Acid Ki=304.9 10.7 M Ki=NB logP=1.29; pKa=3.5 logP=0.2; pKa=5.0 logD(7.4)=-2.5 logD(7.4)=-2.9 INDOLE ACIDS
N
O
OH
N
O
OH Indole-3-butyric Acid 3-Indoleacetic Acid Ki=72.3 12.2 M Ki=92.8 15.6 M logP=2.3 logP=1.4 pKa=17.4 -NH pKa=16.7 -NH 4.8 -COOH 4.8 -COOH logD(7.4)=-0.2 logD(7.4)=-1.2 HETEROARYL ACETIC ACID DERIVATIVES
N
O
O
CH3
HO
CH3 N
O
O
OH Tolmetin Ketorolac Ki= 134080 M Ki=1670 110 M logP=1.6; pKa=3.5 logP=0.8; pKa=3.5 logD(7.4)=-1.4 logD(7.4)=-1.9
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STEROIDS
O
O
CH3
CH3
CH3
H
H
H
O
O
OHCH3
HO
CH3
OH
F
O
O
OH
CH3HO
CH3 CH3
OH
O
O
OH
CH3
CH3
OH
Progesterone Prednisolone Dexamethasone Cortexolone Ki=20.1 4.6 M Ki=95.2 9.4 M Ki=1100 109 M Ki=1570 89 M logP=4.0; pKa=NI logP=1.7; pKa=12.5 logP=2.1; pKa=12.1 logP=2.7; pKa=12.5 logD(7.4)=4.0 logD(7.4)=1.7 logD(7.4)=2.1 logD(7.4)=2.7 BENZODIAZEPINS
N
N
OCH3
Cl
NN+
HN
O-
O
O
N
HN
O
OH
Cl
Cl
H
Diazepam Nitrazepam Lorazepam Ki=1980 87 M Ki=2010 95 M Ki=2100 92 M logP=2.9; pKa=3.4 logP=2.8 logP=2.5 logD(7.4)=2.9 pKa=10.4 pKa=10.8 3.02 0.03 logD(7.4)=2.8 logD(7.4)=2.5 TRICYCLIIC DERIVATIVES
N
R1
N
NH
N
N
Cl
CH3
N
N
CH3
Dibenzazepines Clozapine Mianserin Ki=NB Ki=NB Drug R1 logP=3.5; pKa=8.0 logP=3.8; pKa=7.1 Imipramine Ki=NB; logP=4.5; pKa=9.5; logD(7.4)=2.4 -(CH2)3N(CH3)2 logD(7.4)=2.4 logD(7.4)=2.8 Desipramine Ki=NB; logP=3.9;pKa=10.2; logD(7.4)=1.2 -(CH2)3NHCH3 Trimipramine Ki=NB; logP=4.8; pKa=9.4; logD(7.4)=2.9 - CH2CH2(CH3)CH2N(CH3)2
R1 S
N
CH3
CH3
Dibenzcycloheptenes Dothiepin Ki=NB Drug R1 logP=5.6; pKa=10.09 Amitriptyline Ki=NB; logP=6.1; pKa=9.4; logD(7.4)=4.3 =CH(CH2)2N(CH3)2 logD(7.4)=3.8 Nortriptyline Ki=NB; logP=5.7; pKa=9.7; logD(7.4)=3.1 =CH(CH2)2NHCH3
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-ADRENERGIC BLOCKERS
NH
O
OH
OCH3 CH3
CH3 O
HN
O
H2N
OH
CH3
CH3
NH
OO
O
HN
OH
CH3
CH3
CH3
CH3 O
HN
OH
OH
OH
CH3
CH3CH3
Metoprolol Atenolol Acebutolol Nadolol Ki=NB Ki=NB Ki=NB Ki=NB logP=1.8; pKa=9.56 logP=0.1; pKa=9.5 logP=2.6; pKa=9.5 logP=1.3; pKa=9.7 logD(7.4)=-0.4 logD(7.4)=-2.0 logD(7.4)=0.5 logD(7.4)=-0.8
N NS
N O HN
O
OH
CH3
CH3
CH3
H
HN
OHN
OH
CH3
CH3
O
HN
H2N
HO
OH
CH3 O
HN
OH
CH3
CH3
Timolol Pindolol Labetalol Propranolol Ki=NB Ki=NB Ki=NB Ki=NB logP=-0.2; pKa=13.48 logP=1.9; pKa=9.5 logP=2.9 logP=3.1; pKa=9.5 logD(7.4)=-2.0 logD(7.4)=-0.2 pKa=9.4 logD(7.4)=0.9 7.5 logD(7.4)=0.9 MICELLANEOUS COMPOUNDS
O
N
OH
OHHO
N
N
N
NH
NH
NH
S
CH3
CH3
N
NH
HN
Cl
Cl
Nalbuphine Cimetadine Clonidine Ki=NB Ki=NB Ki=NB logP=2.3 logP=0.4; pKa=6.8 logP=1.5; pKa=8.2 pKa=9.6 logD(7.4)=0.2 logD(7.4)=-0.8 7.2 logD(7.4)=0.4 aNB: No binding detected. bNI: No ionizable groups. Figure S1. The Chemical Structures of Generic Drugs Examined for I-FABP Binding Affinity The I-FABP binding affinity as measured by the ANS fluorescence displacement assay (under the low salt buffer condition) and physicochemical properties of each compound are indicated.
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Figure S2. The 1H,15N HSQC Spectra of apo-I-FABP (red) Superimposed with the 1H,15N HSQC Spectra of holo-Drug Bound I-FABP (A) holo-Fenofibric acid I-FABP, purple (B) holo-Tolfenamic acid I-FABP, yellow (C) holo-Clofibric acid I-FABP, blue.
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Table S1. Membrane Retention Data for the PAMPA Drug Transport Model
Membrane retention at 7h (% initial)
Donor Buffer Buffer
Acceptor Buffer I-FABP
% reduction in membrane retention
I-FABP binding affinity (Ki, M)
Oleic Acid 89.9 3.1 4.86 0.7 94.6 0.06 0.01
Tolfenamic acid
17.4 3.3 1.03 0.2 94.0 2.8 0.7
Progesterone 83.4 2.7 76.4 5.3 8.39 20 4.6
Ibuprofen 1.8 0.2 0.5 0.1 72.2 58 8.4
Diazepam 42.1 0.6 35.8 3.1 14.9 2000 87
Propranolol 11.5 0.5 11.6 0.9 0.86 NBa a NB: No binding detected
