Ojima I. (ed.) Fluorine in Medicinal Chemistry and Chemical Biology
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Index 615
1-(4-fl uorophenyl)-3(R)-[3-(4-fl uorophenyl)-
3(S)-hydroxypropyl]-4(S)-(4-
hydroxyphenyl)-2-azetidinone (ezetimibe)
542
4-fl uoro-phenylglycine 481
[S-[R*,S*-(E)]]-7-[4-(4-fl uorophenyl)-5-
(methoxymethyl)-2,6-bis(1-methylethyl)-
3-pyridinyl]-3,5-dihydroxy-6-heptenoate,
sodium salt (cerivastatin sodium) 532
(E,3R,5R)-7-[4-(4-fl uorophenyl)-2-
(methylmethylsulfonyl-amino)-6-propan-
2-yl-pyrimidin-5-yl]-3,5-dihydroxy-hept-
6-enoate, calcium salt (rosuvastatin
calcium) 574
1-(4-fl uorophenyl)-4-(4-methyl-1-
piperidyl)butan-1-one (melperone) 564
3-[1-[4-(4-fl uorophenyl)-4-oxobutyl]-3,6-
dihydro-2H-pyridin-4-yl]-3H-
benzoimidazol-2-one (droperidol) 540
(E,3S,5R)-7-[3-(4-fl uorophenyl)-1-propan-2-yl-
indol-2-yl]-3,5-dihydroxyhept-6-enoate,
sodium salt (fl uvastatin sodium) 554
1-(4-fl uorophenyl)-4-(4-pyridin-2-ylpiperazin-
1-yl)butan-1-one (azaperone) 586
α-fl uoro-α-phenylsulfi nylacetate 264
4-(2-fl uorophenyl)-1,3,8-trimethyl-6H-
pyrazolo[4,5-f][1,4]diazepin-7-one
hydrochloride (zolazepam hydrochloride)
602
α-fl uoro-α-phosphonoacetate 259, 260
Fluoroplex (5-fl uorouracil) 507–12, 548
4(R)-fl uoroproline (Flp)/4(S)-fl uoroproline (fl p)
14, 219, 427–8
2-(fl uoro-propan-2-yloxyphosphoryl)
oxypropane (isofl urophate) 560
[
18
F]fl uoropropyldihydrotetrabenazine (FP-
DTBZ) 366–8
5-fl uoro-2,4(1H,3H)-pyrimdinedione (5-
fl uorouracil) 507–12, 548
fl uoroquinolones 308
fl uorosulfonyldifl uoroacetate (TFDA) 321, 324
9-fl uoro-11,16,17-trihydroxy-17-(2-
hydroxyacetyl)-10,13-dimethyl-6,7,8,9,10,
11,12,13,14,15,16,17-
dodecahydrocyclopenta[a]phenanthren-3-
one (triamcinolone) 600
9-fl uoro-11β,17,21-trihydroxy-16α-
methylpregna-1,4-diene-3,20-dione
(dexamethasone) 538, 588
9-fl uoro-11β,17,21-trihydroxy-16β-
methylpregna-1,4-diene-3,20-dione 17
valerate (betamethasone valerate) 530,
586
α-fl uoro-α-trimethylsilyl acetate 260
fl uorotryptophan 248, 483
5-fl uorouracil (5-FU) 507–12, 548
fl uorous affi nity separation of peptides 413–15
fl uorous biphasic catalysis 412
fl uorous mixture synthesis (FMS) 336–7,
355–6
examples of 339–55
tags (protecting groups) 337–9, 346, 351
fl uorous small-molecule microarrays 415–16
fl uorous tags
in FMS 337–9, 346, 351
in SPPS 413–15
Fluosim (fl umethasone/fl umethasone acetate)
592
Fluothane (halothane) 560, 596
fl uoxetine 512, 513
fl uoxetine hydrochloride (Prozac/Reconcile)
548, 594
fl uoxymesterone (Halotestin) 548
fl uphenazine decanoate 550
fl uphenazine enanthate (Prolixin Enanthate)
550
fl uphenazine hydrochloride 550
fl uprednisolone (Alphadrol) 550
fl uprostenol sodium (Equimate) 52, 594
fl urandrenolide (Cordran) 550
fl urazepam hydrochloride 552
fl urbiprofen (Ansaid) 552
fl urbiprofen sodium (Ocufen) 552
fl urogestone acetate (Synchro-Mate) 596
fl utamide 552
fl uticasone furoate (Flonase) 552
fl uticasone propionate (Advair) 4, 8, 552
fl uvastatin sodium (Lescol) 554
fl uvoxamine maleate 554
FML (fl uorometholone) 548
FMS see fl uorous mixture synthesis
forane (isofl uorane) 560
FP23 peptide (of gp41) 486–7
FS Shampoo (fl uocinolone acetonide) 546
5-FU (5-fl uorouracil) 507–12, 548
Fudr (fl oxuridine) 542
fulvestrant (Faslodex) 554
fusogenic peptides 466, 486–7
GABA (γ-aminobutanoic acid)
aminotransferase 222
GABA (γ-aminobutyric acid) receptor 424
Garner’s aldehyde 220, 241
gatifl oxacin (Zymar) 554
gauche effect 13–16, 190, 427–8
GBC (betamethasone valerate) 586
GCN4 coiled-coil dimer 405–6, 430–1, 432
gefi tinib (Iressa) 554
gelatinase B (MMP-9) 107
gemcitabine hydrochloride (Gemzar) 554
616 Index
gemifl oxacin mesylate (Factive) 556
Gemzar (gemcitabine hydrochloride) 554
Genesis (triamcinolone acetonide) 600
gene therapy 275
Gentavet (betamethasone valerate) 586
Gentocin (betamethasone acetate) 586
Gentocin Otic (betamethasone valerate) 586
glaucoma, prostenoids for treatment of 53–62
glucose, [
18
F]FDG 365–6, 544
glucuronidation 146
glutamate analogs 67, 317–18
agonists 68, 69–70, 71–82, 92, 318–19, 321
antagonists 68–9, 70–1, 82–92
comparison of fl uorinated and non-
fl uorinated compounds 92–3
glutamate-induced cytotoxicity, tafl uprost and
60
glutamate receptors 68
glutamic acid analogs 214, 221, 222, 228
glutamine analogs 220–1, 233, 241
glutathione 134
glycine 464
glycine reuptake transport system 231
glycolipids, fl uorinated 417
gp41 protein 486–7
gramicidin S 23–4, 286, 434–5, 483–4
green fl uorescent protein (GFP) 437–8
grepafl oxacin hydrochloride (Raxaar) 556
guanidine 302
guanidinium ion of arginine 21
guanosine
2′-deoxy-2′-α-fl uoroguanosine 169
2′FGpG 172–3
dH isostere of 280–1
FddG 167, 183–8
halazepam (Paxipam) 556
halcinonide (Halog) 556
Haldol (haloperidol decanoate/lactate) 558
Haldrone (paramethasone acetate) 568
Halfan (halofantrine hydrochloride) 558
halobetasol propionate (Ultravate) 556
halofantrine hydrochloride (Halfan) 558
Halog (halcinonide) 556
haloperidol 513, 558
haloperidol decanoate (Haldol) 558
haloperidol lactate (Haldol) 558
Halotestin (fl uoxymesterone) 548
halothane (Fluothane) 560, 596
Hansch hydrophobicity parameters 10, 418
hepatitis B, drugs for 183–4
heterocyclic compounds
as core scaffolds in drug discovery 293–6
bicyclic perfl uorinated compounds 300–8
pentafl uoropyridine 296–9, 302–3, 306
perbromofl uoropyridine 299
tetrafl uoropyrimidine 299
FMS 353–5
1,1,1,3,3,3-hexafl uoro-2-
(fl uoromethoxy)propane (sevofl urane)
574, 600
1,1,1,3,3,3-hexafl uoroisopropanol (HFIP) 149
hexafl uoroleucine 220, 221, 431, 432, 435–6
high performance liquid chromatography
(HPLC) 336–7
Hilderbrand–Scatchard solubility parameter (δ)
412–13
histone deacetylase inhibitors 416
HIV
drugs for 190–1
FddA (lodenosine) 167, 177–83, 190–1
FddG 167, 183–8
norcarbovir triphosphate 27
peptide structures
FP23 486–7
TAT 486
reverse transcriptase 188–9, 282–3
HMG-CoA reductase 21
Honor–Wadsworth–Emmons (HWE) reaction
259–60
HPLC (high performance liquid
chromatography) 336–7
Huisgen 1,3-dipolar cycloaddition reaction
375–9
hydantoins, fused-tricyclic 351–4
hydrofl umethiazide (Salutensin) 560
hydrogen bonds 16–18, 278–9, 412
hydrolytic enzyme inhibitors 29–30
hydrophobicity of fl uorine 10–11
protein folding/stability and 394–406, 418,
429–31
hydroxamic acid analogs (MMP inhibitors)
α-CF
3
-α-amino-β-sulfone hydroxamates
104–7
α-CF
3
-malic hydroxamates 100–4
β-fl uoroalkyl-β-sulfonylhydroxamic acids
110–12
syn-2-hydroxy-3-aminobutanoates 227
(2S)-2-hydroxybutanedioic acid (constituent of
sunitinib malate) 576
1-[4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-
5-(trifl uoromethyl)pyrimidine-2,4-dione
(trifl uridine) 580
2-hydroxy-3-pinanone 233
5-hydroxytryptamine-3A (5HT
3A
) receptor 424
hypnotic agents 173–4
hypoglycemic agents 350–1
IFABP (intestinal fatty acid binding protein)
419–20
Index 617
Imagent (perfl ubron) 570
imidate [3,3]-sigmatropic rearrangement 262–4
imidazopyrazine scaffolds 303
imidazopyridine 301–2
immunotherapy 134
Impromen (bromperidol) 532
Inaspine (droperidol) 540
inductive effects 11–13, 425
industrial synthetic requirements 178–9
infl uenza A virus 32
Innovar-Vet (droperidol) 590
insect control agents
DDT-pyrethroid 313–14
pinesaw fl y sex pheromone 342–4
interleukin-2 436
intestinal fatty acid binding protein (IFABP)
419–20
intraocular pressure (IOP), reduction of 53–4,
58–60
Invega (paliperidone) 566
iodonium salts 369–71
Iquix (levofl oxacin) 562
Iressa (gefi tinib) 554
IsoFlo (isofl urane) 596
isofl upredone acetate (Predaf/Neo-Predaf) 596
isofl urane (Forane/Aerrane/IsoFlo) 560, 596
isofl urophate (Floropryl) 560
isoleucine analogs 244, 431, 436
(R)-2,3-O-isopropylideneglyceraldehyde 220,
242–4
isosteres see peptide bond isosteres
Januvia/Janumet (sitagliptin phosphate) 5, 574
juvenile hormone-epoxide hydrolase inhibitors
319
Kenalog (triamcinolone acetonide) 578
ketones, fl uorinated 28–31
KNP 215 analogs 317
Krebs cycle 6
β-lactam synthon method 121–2, 128, 226
lagunapyrone B 347
lansoprazole (Prevacid) 4, 560
lapatinib ditosylate (Tykerb) 560
Lariam (mefl oquine hydrochloride) 564
Larmor frequency of
19
F 497, 498, 503
latanoprost 54, 58, 59
lefl unomide (Arava) 562
Lescol (fl uvastatin sodium) 554
leucine analogs 220, 221, 429–31, 435–6,
436–7
Levaquin (levofl oxacin) 562
levocabastine hydrochloride (Livostin) 562
levofl oxacin (Levaquin) 562
Lexapro (escitalopram oxalate) 542
Lidex (fl uocinonide) 546
linezolid (Zyvox) 562
lipase, in resolution of racemic mixtures
224–6, 324–5
lipids, fl uorinated 417
Lipitor (atorvastatin calcium) 4, 21, 528
lipophilicity of fl uorine 10–11, 400
see also hydrophobicity of fl uorine
Livostin (levocabastine hydrochloride) 562
Locorten (fl umethasone pivalate) 546
lodenosine (FddA) 167, 177–83, 190–1
lomefl oxacin hydrochloride (Maxaquin) 562
Lotrisone (betamethasone dipropionate) 530
lubiprostone (Amitiza) 564
lufenuron (Program/Sentinal/Capstar) 596
Luxiq (betamethasone valerate) 530
LY354740 ((1S,2R,5R,6S)-2-aminobicyclo
[3.1.0]hexane-2,6-dicarboxylic acid) 80,
92
fl uorinated analogs 69–71
lysine analogss 241, 245
lysozyme (bacteriophage lambda) 451–3
Macugen (pegaptanib sodium) 570
magainin(s) 421, 435–6, 484–5
magnetic resonance spectroscopy see MR
spectroscopy
malaria, treatment of see artemisinins
mappicine 340–1
libraries 347–50
marbofl oxacin (Zeniquin) 598
Marquis (ponazuril) 598
matrix metalloproteinases (MMPs) 99–100,
107
α-CF
3
-α-amino-β-sulfone hydroxamate
inhibitors 104–7
CF
3
-barbiturate inhibitors 107–10
α-CF
3
-malic hydroxamate inhibitors 100–4
β-fl uoroalkyl-β-sulfonylhydroxamic acid
inhibitors 110–12
Maxaquin (lomefl oxacin hydrocholoride) 562
MDR see multidrug resistance
Medalon (triamcinolone acetonide) 600
mefl oquine hydrochloride (Lariam) 564
melanogenesis 60–1
melperone 564
membrane peptides/proteins
antimicrobial peptides 23–4, 286, 421–2,
435, 465, 483–5
cell-penetrating peptides 465–6, 485–6
designed 432–4
fusogenic peptides 466, 486–7
structure and orientation 421, 467–9, 471–6,
481–3
618 Index
menthyl group 239–40
mesylate fl uorination in protic solvents 380
metalloproteins
di/trifl uorinated methionine and 455–8
see also matrix metalloproteinases
methanol, in the synthesis of CF
3
artemether
148–50
methionine aminopeptidase (MAP) 458–60
methionine, fl uorinated 458
enzymes binding to 458–60
in peptides/proteins 450–1
lysozyme 451–3
metalloenzymes 455–8
physicochemical properties 449–50
platinum and 454
synthetic methods 448–9
methoxyfl urane (Metofane) 598
2-methoxy-1-phenylethylamine 228
2-[[5-methoxy-1-[4-(trifl uoromethyl)phenyl]
pentylidene]amino]oxyethanamine
(constituent of fl uvoxamine maleate) 554
(2R,3R,4R,5S)-6-methylaminohexane-
1,2,3,4,5-pentol; 2-[[2-methyl-3-
(trifl uoromethyl)phenyl]amino]pyridine-3-
carboxylic acid (fl unixin meglumine) 592
methyl 3-amino-4-polyfl uorophenylbutanoate
215
4-methylbenzenesulfonic acid (constituent of
lapatinib ditosylate) 560
methylene-gem-difl uorocyclopropylglycines
319
1-methyl-N-[(1S)-2-(methyl-
(phenylmethyl)amino)-2-oxo-1-
phenylethyl]-5-[[2-[4-(trifl uoromethyl)
phenyl]benzoy]amino]indole-2-
carboxamide (dirlotapide) 590
1-methyl-3-[3-methyl-4-[4-
(trifl uoromethylsulfonyl)phenoxy]phenyl]-
1,3,5-triazinane-2,4,6-trione (ponazuril)
598
2-methyl-N-[4-nitro-3-(trifl uoromethyl)phenyl]
propanamide (fl utamide) 552
N-methyl-3-phenyl-3-[4-(trifl uoromethyl)
phenoxy]propan-1-amine hydrochloride
(fl uoxetine hydrochloride) 548, 594
4-[5-(4-methylphenyl)-3-(trifl uoromethyl)-1H-
pyrazol-1-yl] benzenesulfonamide
(celecoxib) 532
10-[3-(4-methylpiperazin-1-yl)propyl]-2-
(trifl uoromethyl)phenothiazine
dihydrochloride (trifl uoperazine
hydrochloride) 580
2-[[3-methyl-4-(2,2,2-trifl uoroethoxy)pyridin-2-
yl]methylsulfi nyl]-1H-benzoimidazole
(lansoprazole) 4, 560
5-methyl-N-[4-(trifl uoromethyl)phenyl]-1,2-
oxazole-4-carboxamide (lefl unomide)
562
Metofane (methoxyfl urane) 598
Met-tRNA synthetase 458
mGluRs (metabotropic glutamate receptors)
68–9
MGS0008 ((1S,2S,3S,5R,6S)-2-amino-3-
fl uorobicyclo[3.1.0]hexane-2,6-
dicarboxylic acid) 69–70, 71–2, 77–9, 80,
92
MGS0022 ((1R,2S,5R,6R)-2-amino-6-fl uorobic
yclo[3.1.0]hexane-2,6-dicarboxylic acid)
69–70, 72–3, 79, 92
MGS0028 ((1R,2S,5S,6S)-2-amino-6-fl uoro-4-
oxobicyclo[3.1.0]hexane-2,6-dicarboxylic
acid monohydrate) 70, 73–7, 79–82
MGS0039 ((1R,2R,3R,5R,6R)-2-amino-3-(3,4-
dichloro-benzyloxy)-6-fl uorobicyclo[3.1.0]
hexane-2,6-dicarboxylic acid) 68–9, 82–7,
92
prodrugs of 71, 87–92, 92–3
MGS0210 (prodrug of MGS0039) 71, 90,
92
microtubules, effect of taxoids on 118,
119
midazolam hydrochloride 564
mimic effects 6–7, 26–8
see also peptide bond isosteres
Minizide (polythiazide) 572
miscibility of fl uorocarbons 412–13
Mitsunobu reaction 145
MMP see matrix metalloproteinases
model amphipathic peptide 485–6
“molecular rulers” 281–2
monoamine oxidase inhibitors 319
monoclonal antibodies 134–5
monofl uoromethionine 448
moxifl oxacin hydrochloride (Avelox/Vigamox)
564
MR spectroscopy (magnetic resonance) using
19
F 32–4, 495–503, 517–18
of the brain 503, 512–13
comparison of in vitro, in vivo and ex vivo
results 503–7, 513, 516–17
data analysis 515–17
5-fl uorouracil 507–12
long-term biodistribution studies 513–15
MS-073 analogs (MDR reversal agents)
314–15
MSI-103 antimicrobial peptide 485
multidrug resistance (MDR)
reversal by difl uorocyclopropanes 314–15
taxoids and 119–20, 122, 123, 126, 131
to antimalarial drugs 141
Index 619
murisolin 341–2
Mykacet (triamcinolone acetonide) 578
Mymethasone (dexamethasone) 538
N-[1-(R)-(-)-(1-naphthyl)ethyl]-3-[3-
(trifl uoromethyl)phenyl]-1-aminopropane
hydrochloride (cinacalcet hydrochloride)
532
Naquasone (dexamethasone) 588
Nararel (fl unisolide) 546
natural fl uorinated compounds 3
negative hyperconjugation 16
Neo-Aristovet (triamcinolone acetonide) 600
Neo-Predaf (isofl upredone acetate) 596
Neo-Synalar (fl uocinolone acetonide) 594
Nexavar (sorafenbin tosylate) 576
nicotinic acetylcholine receptor (nAChR) 424
nifl umic acid 500, 513–14
nilutamide (Nilandron) 566
nitisinone (Orfadin) 566
nitroreductase 420
2-[2-nitro-4-(trifl uoromethyl)benzoyl]
cyclohexane-1,3-dione (nitisinone) 566
NMR spectroscopy (nuclear magnetic
resonance) using
19
F 32, 418–19, 463–4,
469–76
synthesis of markers
19
F-labeled amino acids 464–5, 477
peptides 477–83
systems studied
antimicrobial peptides 421–2, 483–5
DAGK 421
IFABP 419–20
lysozyme (phage) 451–3
nitroreductase 420
taxoid–tubulin binding 131–3
NOE spectroscopy (nuclear Overhauser effect)
500, 509–10
norcarbovir triphosphate 27
norfl oxacin (Noroxin) 566
Nortran (trifl uomeprazine maleate) 600
Noxafi l (posaconazole) 572
nucleocidin 166
nucleosides 165, 166
azanucleosides 207–9
biological activity 188–91
carbocyclic 209–10
difl uorocyclopropane isosteres 319–20
difl uoromethylenated 201–10
difl uorotoluene isostere 25–6
fl uoroarene isosteres 277–83
purines
2′-deoxy-2′-α-fl uoro analogs 168–73,
188–90
2′-deoxy-2′-β-fl uoro analogs 174–7
FddA 167, 177–83, 190–1
FddG 167, 183–8
pyrimidines
2′-deoxy-2′-α-fl uoro analogs 167–8,
173–4, 188
2′-deoxy-2′-β-fl uoro analogs 174
MR spectroscopy of 5-FU 507–12
thionucleosides 205–7
Nufl or (fl orfenicol) 592
1,1,1,2,2,3,3,3-octafl uoropropane (perfl utren)
570
7-[(4aS,7aS)-1,2,3,4,4a,5,7,7a-
octahydropyrrolo[3,4-b]pyridin-6-yl]-1-
cyclopropyl-6-fl uoro-8-methoxy-4-
oxoquinoline-3-carboxylic acid
hydrochloride (moxifl oxacin
hydrochloride) 564
Ocufen (fl urbiprofen sodium) 552
ofl oxacin (Ocufl ox) 566
Olux (clobetasol propionate) 536
Oracort (triamcinolone acetonide) 578
Oralone (triamcinolone acetonide) 578
Orap (pimoxide) 570
orbifl oxacin (Orbax) 598
Orfadin (nitisinone) 566
organometals
Me
2
CuLi 264–6, 267
in synthesis of [
18
F]FDOPA 372–3
trimethyltin 374
organophosphorus reagents 259–60
organosilyl reagents 260
Otomax (betamethasone valerate)
586
Overmann rearrangement 262–4
oxazolidines 229–30
oxazolidinones 234
[2-oxo-2-[(2S,4S)-2,5,12-trihydroxy-4-[5-
hydroxy-6-methyl-4-[(2,2,2-
trifl uoroacetyl)amino]oxan-2-yl]oxy-7-
methoxy-6,11-dioxo-3,4-dihydro-1H-
tetracen-2-yl]ethyl] pentanoate
(valrubicin) 582
p38 kinase inhibitors 298–9
paclitaxel 118–19, 123, 131–2
paliperidone (Invega) 566
Panavet (triamcinolone acetonide) 600
Panolog (triamcinolone acetonide) 600
pantoprazole sodium (Protonix) 568
paramethasone acetate (Haldrone) 568
paroxetine hydrochloride (Paxil) 568
paroxetine mesylate (Pexeva) 568
passifl oricins 344–7
Paxil (paroxetine hydrochloride) 568
620 Index
Paxipam (halazepam) 556
pegaptanib sodium (Macugen) 570
Penetrex (enoxacin) 542
7α-[9-(4,4,5,5,5-pentafl uoropentylsulfi nyl)
nonyl]estra-1,3,5-(10)-triene-3,17β-diol
(fulvestrant) 554
pentafl uorophenylalanine (f
5
-Phe) 426,
434
pentafl uoropyridine 296–9, 302–3, 306
pepstatin 267
peptide bond isosteres 22, 257–8, 287
fl uoro-olefi ns (ψ[CF
=
CH]) 23–4
DPP IV inhibitors 272–5
fl uoroarenes as nucleoside base mimics
277–83
peptide-nucleic acid 275–7
Substance P 23, 262, 271
synthesis 22, 23, 258–70
thermolysin inhibitors 271–2
trifl uoroethylamines (ψ[NHCH(CF
3
)])
24–5
trifl uoromethylated alkenes
(ψ[CH(CF
3
)
=
CH]) 283–6
peptide-nucleic acid (PNA) 275–7
peptidyl-glycylleucine-carboxyl-amide (PGLa)
421, 484–5
perbromofl uoropyridine 299
perfl exane 570
perfl ubron 570
perfl uorinated heterocyclic compounds
295–6
bicyclic compounds 300–8
pentafl uoropyridine 296–9, 302–3, 306
perbromofl uoropyridine 299
tetrafl uoropyrimidine 299
perfl uoroalkanesulfonyl fl uorides 182–3
perfl uoroalkylated amino acids 231
perfl uoroalkyl chains in FMS 336
perfl uorobenzene 425–6
perfl uoropolymethylisopropyl ether 570
perfl utren (Defi nity) 570
Pet Derm (dexamethasone) 588
Peterson reaction 260
PET (positron emission tomography) using
18
F
34–6, 361, 422, 500
Pexeva (paroxetine mesylate) 568
PGLa (peptidyl-glycylleucine-carboxyl-amide)
421, 484–5
pharmacokinetics
artemisinins 142, 151, 157–8
fl uoxetine 512, 513
5-FU 508–12
long-term biodistribution studies 513–15
MGS0028 80–2
MGS0039 87
MGS0039 prodrugs 87–92
MR spectroscopy and 32–4, 503
tafl uprost 61–2
taxoids 128
phenylalanine analogs 217, 228, 426, 434
see also dopamine
(S)/(R)-1-phenylethylamines 226–9
phosphate, difl uoromethylene isostere 26–7
phosphorane 260
photoirradiation, DNA cleavage using
difl uorocyclopropanes 319, 326–8
physicochemical properties
of drug candidates 292
of fl uorine 6–21, 412–13, 496–7
pimozide (Orap) 570
pinesaw fl y sex pheromone 342–4
piperazinedione-fused heterocyclic scaffold
353
N-(2-piperidylmethyl)-2,5-bis(2,2,2-
trifl uoroethoxy) benzamide (fl ecainide
acetate) 542
pK
a
, effect of F on 11–12
platinum, complexed with methionine 454
PNA (peptide-nucleic acid) 275–7
polar C–F bond–protein interactions
18–21
polar hydrophobicity 399, 407
polytetrafl uoroethylene 570
polythiazide (Renese/Minizide) 572
ponazuril (Marquis) 598
posaconazole (Noxafi l) 572
positron emission tomography (PET) using
18
F
34–6, 361, 422, 500
Predaf (isofl upredone acetate) 596
pregna-1,4-diene-3,20-dione,21-(acetyloxy)-
16,17-[cyclopentylidenebis (oxy)]-9-
fl uoro-11-hydroxy-,(11β,16α)
(amcinonide) 528
pregna-1,4-diene-3,20-dione,9-fl uoro-11,21-
dihydroxy-16-methyl-, (11β, 16α)-
(desoximetasone) 538
pregna-1,4-diene-3,20-dione,9-fl uoro-11,21-
dihydroxy-16-methyl-17-[(1-
oxopentyl)oxy]-,(11β,16β) (betamethasone
valerate) 530, 586
Prevacid (lansoprazole) 4, 560
privileged structures in drug discovery
293–5
Program (lufenuron) 596
proline analogs
azanucleoside synthesis and 207–9
collagen stability and 426–9
difl uoroproline dipeptides 249
gauche effect and 14, 427–8
synthesis of 214, 219, 241, 244, 245
Index 621
Prolixin Enanthate (fl uphenazine enanthate)
550
propan-2-yl (Z)-7-[(1R,2R,3R,5S)-3,5-
dihydroxy-2-[(E,3R)-3-hydroxy-4-[3-
(trifl uoromethyl)phenoxy]but-1-
enyl]cyclopentyl]hept-5-enoate
(travoprost) 54, 578
Propulsid (cisapride monohydrate) 534
Proquin XR (ciprofl oxacin hydrochloride) 534
prostanoids 49
glaucoma therapy and 53–4, 58–62
increased stability of fl uorinated analogs
52–3
receptors 49–51, 57
tafl uprost 55–62
protegrin-1 (PG-1) 421–2
proteomics 415
protic solvents in nucleophilic
18
F-fl uorinations
379–82
Protonix (pantoprazole sodium) 568
Prozac (fl uoxetine hydrochloride) 548
Psorcon (difl orasone diacetate) 540
psychiatric conditions, drugs for
brain MR spectroscopy 512–13
glutamate analogs 68–9, 79–80, 86–7
purifi cation methods using fl uorous tags
336–7, 413–15
9H-purin-6-amine, 2-fl uoro-9-(5-0-phosphono-
β-d-arabinofuranosyl)(2-fl uoro-ara-AMP)
(fl udarabine phosphate) 544
purine nucleosides
2′-deoxy-2′-α-fl uoro analogs 168–73,
188–90
2′-deoxy-2′-β-fl uoro analogs 174–7
FddA 167, 177–83, 190–1
FddG 167, 183–8
puromycin 171–2, 189–90
pyridine derivatives in perfl uorinated
heterocyclic systems 296–308
pyrido[2,3-b]pyrazine scaffolds 303–6
pyrido[3,4-b]pyrazine scaffolds 303
pyridovericin 339–40
pyrimidine nucleosides
2′-deoxy-2′-α-fl uoro analogs 167–8, 173–4,
188
2′-deoxy-2′-β-fl uoro analogs 174
MR spectroscopy of 5-FU 507–12
see also tetrafl uoropyrimidine
pyroglutamic acid 244
pyroglutaminol 222
quasi-racemic FMS 337
examples of 339–41, 347
quazepam (Doral) 572
Quixin (levofl oxacin) 562
racemic mixtures
enzymatic resolution of 224–6, 324–5
synthesis of racemic amino acids 246–9
radiofrequency (RF) coils 502–3, 516
radiopharmaceuticals, (
18
F) 34–6, 361–2
“click” chemistry 376–9
electrophilic fl uorinations 369, 371–3, 374
isotope production 362, 371
nucleophilic fl uorinations 364–9, 373–4
in protic solvents 379–82
prosthetic groups 369, 371
radiolytic decomposition 363
specifi c activities 362–3, 364, 367–8, 371
yields 363–4, 366, 370, 371, 379, 382
rapid analogue synthesis (RAS) 293
Raxaar (grepafl oxacin hydrochloride) 556
Reconcile (fl uoxetine hydrochloride) 594
REDOR (rotational echo double-resonance)
analysis of taxoid–tubulin binding
131–3
relaxation times in MR spectroscopy 499–500,
505, 516
Renese (polythiazide) 572
renin inhibitors 30–1, 434
replicase activity of coiled-coil polypeptides
399–401
resistance to drugs see multidrug resistance
respiration compensation in MR spectroscopy
497–8
Retisert (fl uocinolone acetonide) 546
reverse transcriptase 27, 188–9, 282–3
RF (radiofrequency) coils 502–3, 516
ribonucleotide reductase 424
ribosomal protein L9 429–30
riluzole (Rilutek) 572
risperidone (Risperdal/Risperdal Consta) 4,
574
RNA
containing 2′-deoxy-2′-α-fl uoronucleosides
188–9
duplexes containing fl uoroarene isosteres
279–80
RNases 172
Romazicon (fl umazenil) 546
romifi dine hydrochloride (Sedivet) 598
rosuvastatin calcium (Crestor) 574
Rules of 5 (RO5) 292
safety considerations
MR spectroscopy 498
in synthetic methods 108, 178–9, 188
Saluron (hydrofl umethiazide) 560
Salutensin (hydrofl umethiazide) 560
Sarafem (fl uoxetine hydrochloride) 548
sarafl oxacin hydrochloride (SaraFlox) 598
622 Index
schizophrenia, drugs for see antipsychotic
agents
Sedivet (romifi dine hydrochloride) 598
Sensipar (cinacalcet hydrochloride) 532
Sentinal (lufenuron) 596
serine 221–2
serine protease inhibitors 29–30, 272–5
serotonin 424
sevofl urane (Ultane/Sojourn/SevoFlo) 574,
600
Seyferth’s reagent 322, 324
signal-to-noise ratio (SNR) (in MR
spectroscopy) 498–9, 500, 509–10, 517
silver ions in substitution reactions with
methanol 148–9
sitafl oxacin 514–15
sitagliptin phosphate (Januvia/Janumet) 5, 574
Slentrol (dirlotapide) 590
small-molecule microarrays (SMMs) 415–16
sodium fl uoride 574
sodium monofl uorophosphate 574
Sojourn (sevofl urane) 574
solid-phase synthesis 336
SPPS 392, 413–15, 478–80
Soltara (tecastemizole) 503–7, 513
solubility of fl uorocarbons 412–13
sorafenbin tosylate (Nexavar) 576
sparfl oxacin (Zagam) 576
spatial localization (MR spectroscopy) 500–3
sphingomyelinase (SMase) inhibitors 27
SPPS (solid-phase peptide synthesis) 392,
413–15, 478–80
SR-4554 (tissue hypoxia probe) 515
statine 31
Stelazine (trifl uoperazine hydrochloride) 580
stereospecifi c nucleophilic substitution in
amino acid synthesis 219–20, 239, 247
steric effects 8–10, 395, 418, 429, 431
Stresnil (azaperone) 586
Substance P 23, 262, 271
sulfi namides 234–6
sulfonium ions 186–8
β-sulfonylhydroxamic acids, fl uorinated (MMP
inhibitors) 110–12
sulfoxide-elimination reaction 264
sulfur inversion with methionine–platinum
complexes 454
sulfur tetrafl uoride (SF
4
) 108, 188
sulindac (Clinoril) 576
sunitinib malate (Sutent) 576
Sustiva (efavirenz) 5, 540
Sutent (sunitinib malate) 576
Symbax (fl uoxetine hydrochloride) 548
Synalar (fl uocinolone acetonide) 546, 594
Synchro-Mate (fl urogestone acetate) 596
Synotic (fl uocinolone acetonide) 594
Synsac (fl uocinolone acetonide) 594
Taclonex (betamethasone dipropionate) 530
tafl uprost 55–62
tags see fl uorous tags
Tambocor (fl ecainide acetate) 542
taxoids 32, 118–20
antibody conjugates 134–5
C-3′-CHF
2
/CF
3
taxoids 121–3, 132
C-3′-difl uorovinyl-taxoids 128–31, 132–3
C-2-(3-fl uorobenzoyl)-C-seco-taxoids 123–8
tubulin binding studies 131–3
TCA cycle 6
tecastemizole 503–7, 513
tecomanine analogs 350–1
Telazol (zolazepam hydrochloride) 602
Temovate (clobetasol propionate) 536
tensors in NMR spectroscopy 470–1
Tesoprel (bromperidol) 532
1,1,1,2,2,3,3,4,4,5,5,6,6,6-tetradecafl uorohexane
(perfl exane) 570
(±)1,2,2,2-tetrafl uoroethyl difl uoromethyl ether
(desfl urane) 538
tetrafl uoropyrimidine 299
tetraisopropyldisiloxan-1,3-diyl (TIDS) diol-
protecting group 170
TFM see trifl uoromethionine
thermolysin inhibitors 271–2
thermostable enzymes 436–7
thionucleosides 205–7
threonine analogs 214, 215
thrombin inhibitors 18–21
thymidine isosteres 25–6, 277, 281
thymidyl-PNA 276–7
ticarbodine (Tribodine) 600
TIDS (tetraisopropyldisiloxan-1,3-diyl) diol-
protecting group 170
tin (destannylation) 374
tipranavir (Aptivus) 578
Tobrasone (fl uorometholone acetate) 546
Topagen (betamethasone valerate) 586
Topicort (desoximetasone) 538
Toptic (fl umethasone) 592
tosylate fl uorination in protic solvents 380
transcription 189
travoprost (Travatan/Travatan Z) 54, 578
Tresaderm (dexamethasone) 588
Triacet (triamcinolone acetonide) 578
trialkylaluminum 267–9
triamcinolone (Aristova) 600
triamcinolone acetonide 578, 600
triamcinolone hexacetonide (Aristospan) 580
triazole in Huisgen 1,3-dipolar cycloaddition
reaction 375–6, 377
Index 623
Tribodine (ticarbodine) 600
2,4,6-tribromo-3,5-difl uoropyridine 299
Triclosan (sodium fl uoride) 574
tricyclic 2-pyridone scaffold 306, 308
Triderm (triamcinolone acetonide) 578
triethylamine trihydrogenfl uoride 180, 182
trifl uomeprazine maleate (Nortran) 600
trifl uoperazine hydrochloride (Stelazine) 580
trifl uoroacetic acid 478–9
trifl uoroalanine 215, 238
α-allylated 246–7
dipeptides 248
in
19
F NMR spectroscopy 479
trifl uoroalkyl ketones 29–30
trifl uoroethylamine (peptide bond isostere)
24–5
(S)-trifl uoroethylglycine (TfeGly), in coiled-
coil proteins 395, 397–8, 400, 404, 405
6-trifl uoroethyl-l-lysine 245
trifl uoroisoleucine 244, 431, 436
trifl uoroleucine 429–31, 435, 436–7
trifl uoromethionine (TFM) 448
enzymes binding 458–60
incorporation into peptides/proteins 450–1
lysozyme (phage) 451–3
metalloenzymes 455–8
physicochemical properties 449–50
platinum and 454
synthesis 449
6-(trifl uoromethoxy)-1,3-benzothiazol-2-amine
(riluzole) 572
trifl uoromethyl (CF
3
–) 100
hydrogen bonding 16–17
hydrophobicity 10–11, 418, 429–31
in
19
F NMR spectroscopy 470–1
steric effects 8–9, 395, 418, 429, 431
2-trifl uoromethylalanine 229–30, 237–8,
482–3
trifl uoromethylalkenes 215, 283–4
α-trifl uoromethyl-α-amino-β-sulfone
hydroxamates (MMP inhibitors) 104–7
trifl uoromethyl artemisinin analogs
artemether 146, 147–51
artesunate 152
dihydroartemisinin 146–7, 150, 151
with polar groups at C-16 153–8
trifl uoromethyl-barbiturate inhibitors of MMPs
107–10
3-trifl uoromethylbicyclopentylglycine 482
trifl uoromethylcoronamic acid 247
α-trifl uoromethyl-malic hydroxamates (MMP
inhibitors) 100–4
4-[3-[2-(trifl uoromethyl)10H-phenothiazin-10-
yl]propyl]-1-piperazineethanol decanoate
(fl uphenazine decanoate) 550
2-[4-[3-[2-(trifl uoromethyl)phenothiazin-10-
yl]propyl]piperazin-1-yl]ethanol
dihydrochloride (fl uphenazine
hydrochloride) 550
2-[4-[3-[2-(trifl uoromethyl)phenothiazin-10-
yl]propyl]piperazin-1-yl]ethyl heptanoate
(fl uphenazine enanthate) 550
5-[[(2R,3S)-2-[(1R)-1-[3,5-bis-(trifl uoromethyl)
phenyl]ethoxy]-3-(4-fl uorophenyl)-4-
morpholinyl]methyl]-1,2-dihydro-3H-
1,2,4-triazol-3-one (aprepitant)
528
4-trifl uoromethylphenylglycine 481
(5α,17β)-N-(2,5 bis(trifl uoromethyl)phenyl)-3-
oxo-4-azaandrost-1-ene-17-carboxamide
(dutasteride) 540
trifl uoromethylproline 244, 245
2,8-[bis(trifl uoromethyl)quinolin-4-yl]-[(2R)-2-
piperidyl]methanol hydrochloride
(mefl oquine hydrochloride) 564
C-3′-trifl uoromethyl taxoids 121–3, 132
trifl uoromethyltryptophan 248
(S)-trifl uoropropene oxide 224
4,4,4-trifl uorothreonine 215
trifl uorovaline 244, 429–31
trifl upromazine (Vesprin) 580
trifl upromazine hydrochloride (Vetame) 602
trifl uridine (Viroptic) 580
Tri-Luma (fl uocinolone acetonide) 546
trimethyltin 374
N,N,β-trimethyl-2-(trifl uoromethyl)-10H-
phenothiazine-10-propiamine maleate
(trifl uomeprazine maleate) 600
Tri-Otic (betamethasone valerate) 586
trovafl oxacin mesylate (Trovan) 580
Trovan (alatrofl oxacin/trovafl oxacin mesylate)
528, 580
Truvada (emtricitabine) 542
trypsin, resistance to cleavage by 436
tryptophan analogs 248, 483
in ligand–receptor binding studies 424
tubulin 118, 119, 123, 131–3
Tykerb (lapatinib ditosylate) 560
tyrosine analogs 424
tyrosine kinase inhibitors 339–40
ubiquitin 429
Ultane (sevofl urane) 574
Ultravate (halobetasol propionate) 556
unoprostone 53
uracil analogs 209–10
5-fl uorouracil 507–12, 548
uridine analogs 167–8, 173–4, 188, 281,
282–3
Uticort (betamethasone benzoate) 530
624 Index
valine analogs 244, 429–31, 434, 435
Valnac (betamethasone valerate) 530
valrubicin (Valstar) 582
Vaniqa (efl ornithine hydrochloride) 540
vesicular monoamine transporter type 2
(VMAT2) 366
Vesprin (trifl upromazine) 580
Vetalog (triamcinolone acetonide) 600
Vetame (trifl upromazine hydrochloride)
602
Vetro-Max(betamethasone valerate) 586
Vfend (voriconazole) 582
Vigamox (moxifl oxacin hydrochloride) 564
Viroptic (trifl uridine) 580
vitamin D
3
7
Voren (dexamethasone-21-isonicotinate) 590
voriconazole (Vfend) 582
Vytorin (ezetimibe) 542
Xeloda (capecitabine) 34, 510, 532
Zagam (sparfl oxacin) 576
Zeniquin (marbofl oxacin) 598
Zetia (ezetimibe) 542
zinc metalloproteases 455
see also matrix metalloproteinases (MMPs)
zolazepam hydrochloride (Telazol) 602
Zonometh (dexamethasone) 588
Zymar (gatifl oxacin) 554
Zyvox (linezolid) 562