Ojima I. (ed.) Fluorine in Medicinal Chemistry and Chemical Biology

72 Fluorine in Medicinal Chemistry and Chemical Biology

Scheme 3.1 Synthesis of (+) - 6a (MGS0008) and its congeners (1). Reagents and conditions:

(a) (i) LHMDS, TMSCl, THF, (ii) (PhSO

2

)

2

NF, CH

2

Cl

2

; (b) (NH

4

)

2

CO

3

, KCN, EtOH, H

2

O; (c)

60% aq. H

2

SO

4

, 2.5 or 3.0 M aq. NaOH; (d) 2 M aq. NaOH; (e) ( R ) - PhCH(NH

2

)Me,

acetone, H

2

O and then 1 M aq. HCl.

presence of Triton B to yield epoxide ( ± ) - 21 - 1 . Ethyl ester ( ± ) - 21 - 1 was transformed to

2,4 - dimethyl - 3 - pentyl ester ( ± ) - 21 - 2 in two steps to avoid hydrolysis and transesteriﬁ ca-

tion of the ethyl ester under the ﬂ uorination conditions. Thus, ( ± ) - 21 - 1 was hydrolyzed

under basic conditions (92% yield), followed by esteriﬁ cation with 2,4 - dimethyl - 3 -

pentanol in the presence of dicyclohexylcarbodiimide (DCC) to give ( ± ) - 21 - 2 , which

was used in the next step without puriﬁ cation. The nucleophilic ﬂ uorination of epoxide

( ± ) - 21 - 2 with potassium hydrogen diﬂ uoride [48] in ethylene glycol yielded ﬂ uoroenone

( ± ) - 22 . The hydrogenation of ( ± ) - 22 over palladium on carbon proceeded in a highly ste-

reoselective manner to give ( ± ) - 17a - 2 (48% yield for three steps). Fluoroketone ( ± ) - 17a - 2

was converted to optically pure (+) - 6a in a four - step process: (i) formation of hydantoin

( ± ) - 18a - 2 under the Bucherer – Bergs conditions (75% yield); (ii) selective hydrolysis of

the ester moiety with 48% aqueous HBr to give ( ± ) - 19a - 2 (82% yield); (iii) optical resolu-

tion of ( ± ) - 19a - 2 with ( R ) - 1 - phenylethylamine afforded optically pure hydantoin (+) - 19a - 2

(48% yield, > 99% ee); and (iv) hydrolysis of (+) - 19a - 2 under acidic conditions to give

(+) - 6a (MGS0008) (74% yield).

3.4.2 Synthesis of ( − ) - 7a ( MGS 0022)

Racemic ( ± ) - 7a and optically pure (+) - 7a and ( − ) - 7a (MGS0022) were originally synthe-

sized from ﬂ uorobicyclo[3.1.0]cyclohexanecarboxylates ( ± ) - 25 , (+) - 25 , and ( − ) - 25 ,

Fluorinated Conformationally Restricted Glutamate Analogues 73

Scheme 3.2 Synthesis of (+) - 6a (MGS0008) and its congeners (2). Reagents and conditions:

(a) (i) LHMDS, TMSCl, TFA, (ii) Pd(OAc)

2

, MeCN; (b) TBHP, Triton B, PhMe; (c) (i) 2 M

aq. NaOH, (ii) (i - Pr)

2

CHOH, DCC, DMAP, CHCl

3

; (d) KF - HF, ethylene glycol, (e) H

2

, 5%

Pd/C, EtOH; (f) (NH

4

)

2

CO

3

, KCN, EtOH, H

2

O; (g) 48% HBr.

respectively, through (i) hydrolysis of the ethyl ester moieties of ( ± ) - 25 , (+) - 25 , and ( − ) - 25 ,

(ii) formation of hydantoins under Bucherer – Bergs conditions (99%, 88%, and 90% yields

(two steps), respectively), and (iii) hydrolysis of hydantoins ( ± ) - 25 (34% yield), (+) - 25

(72% yield), and ( − ) - 25 (73% yield), under acidic conditions (see Scheme 3.2 ) [15] . The

key intermediate ( ± ) - 25 was synthesized by Cu(TBS) - catalyzed (TBS = N - tert - butylsali-

cylaldimine) intramolecular cyclopropanation of diazoketo - ﬂ uoroalkenoate 24 , which was

prepared from 23 through reaction with oxalyl chloride and then diazomethane (27% total

yield from 23 to 25 ) [49, 50] . Effective optical resolution of ( ± ) - 25 was achieved using

chiral HPLC. Enantioselective intramolecular cyclopropanation of 24 was also examined

using chiral copper catalysts. Among the catalysts examined, the Cu(II) complex with

( S ) - ( − ) - 2,2 ′ - isopropylidenebis(4 - phenyl - 4,5 - dihydro - 1,3 - oxazole) was found to be the

best, yielding ( − ) - 26 with up to 65% ee [42] .

3.4.3 Synthesis of (+) - 7b ( MGS 0028)

Racemic ( ± ) - 7b as well as optically pure (+) - 7b (MGS0028) and ( − ) - 7b were originally

synthesized via hydroxy - keto compounds ( ± ) - 29 , (+) - 29 , and ( − ) - 29 , respectively (see

74 Fluorine in Medicinal Chemistry and Chemical Biology

Scheme 3.4 ) [15] . The key intermediates ( ± ) - 29 and (+) - 29 were prepared from the corre-

sponding ( ± ) - 25 and (+) - 25 in three steps: (i) reaction with TMSCl and LHMDS, followed

by dehydrosilylation catalyzed by palladium acetate (89% and 89% yields), (ii) stereose-

lective epoxidation by TBHP in the presence of Triton B (98% and 88% yields), and (iii)

regioselective reduction of α , β - epoxy ketone ( ± ) - 28 with benzeneselenol, which was

generated in situ from diphenyl diselenide (PhSe)

2

and sodium borohydride in the presence

of acetic acid (76% and 71% yields). Hydroxyketones ( ± ) - 29 and (+) - 29 were converted

to their tert - butyldimethylsilyl (TBS) ethers, followed by thioketalization (the TBS – O

bond was cleaved during the work - up) to give ( ± ) - 30 (85% yield) and (+) - 30 (94% yield),

respectively. Hydroxythioketals ( ± ) - 30 and (+) - 30 were oxidized with dimethyl sufoxide

(DMSO) and DCC in the presence of pyridine and triﬂ uoroacetic acid to afford the corre-

sponding ketones (85% and 76% yields, respectively). The resulting ketone ( ± ) - 31 , was

converted to ( ± ) - 7b (12% yield from ( ± ) - 32 ), in three steps via ( ± ) - 32 (79% yield) using

a protocol similar to that described above for ( ± ) - 6 (see Scheme 3.2 ). Also, optically active

(+) - 7b (MGS0028) (45% yield, from highly polar isomer 33 ) and ( − ) - 7b (28% yield, from

slightly polar isomer 33 ) were obtained by separating the diastereomers of hydantoin -

amides 33 (highly polar isomer 33 : 46% yield and slightly polar isomer 33 : 46% yield,

from ( ± ) - 32 ), which were prepared by coupling ( ± ) - 32 with ( R ) - (+) - 1 - phenylethylamine

(see Scheme 3.4 ).

Next, process chemistry for the practical synthesis of 7b (MGS0028) is discussed

(Schemes 3.5 – 3.7) [42 – 45] . First, the synthesis of key intermediate (+) - 29 from racemic

acetoxycyclopentene ( 34 ) is shown in Scheme 3.5 [43] . The key reaction in this approach

was Trost ’ s asymmetric allylic alkylation reaction of ethyl 2 - ﬂ uoroacetoacetate with 34 ,

which afforded 35 in high yield and high enantioselectivity, especially when a bulky tetra -

n - hexyl ammonium bromide was used as a phase - transfer reagent (89% yield, 94 – 96%

Scheme 3.3 Synthesis of ( − ) - 7 (MGS0022) and its congeners. Reagents and conditions: (a)

(i) (COCl)

2

, hexane, (ii) CH

2

N

2

, Et

2

O; (b) Cu(TBS)

2

, PhH; (c) chiral HPLC; (d) (i) 1 M aq.

NaOH, (ii) KCN, (NH

4

)

2

CO

3

, EtOH, H

2

O; (e) 60% H

2

SO

4

.

Fluorinated Conformationally Restricted Glutamate Analogues 75

Scheme 3.4 Synthesis of (+) - 7b (MGS0028) and its congeners. Reagents and conditions:

(a) (i) LHMDS, TMSCl, THF, (ii) Pd(OAc)

2

, MeCN; (b) TBHP, Triton B, PhMe; (c) (PhSe)

2

,

NaBH

4

, AcOH, EtOH; (d) (i) TBSCl, imidazole, DMF, (ii) HS(CH

2

)

2

SH, BF

3

- Et

2

O, CHCl

3

; (e)

DMSO, DCC, Py, TFA; (f) (i) 1 M aq. NaOH, (ii) KCN, (NH

4

)

2

CO

3

, EtOH, H

2

O; (g) (i) ( R ) -

(+) - PhCH(NH

2

)CH

3

, EDC - HCl, HOBt, DMF, (ii) chromatography on silica gel. (h) 60%

H

2

SO

4

.

ee). Cleavage of the acetyl group of 35 , diastereoselective epoxidation via bromohydrin

( cis : trans = 8 : 1) and intramolecular epoxide opening, followed by oxidation with 1 -

hydroxy - 1,2 - benziodoxal - 3(1 H ) - one - 1 - oxide (IBX) gave intermediate (+) - 25 [43] . Ketone

(+) - 25 was converted to enone (+) - 27 in ﬁ ve steps: (i) bromination of (+) - 25 (100% yield),

(ii) azeotropic ketalization (92% yield), (iii) dehydrobromination, (iv) deketalization (92%

yield for two steps), and (v) treatment with diazomethane (90% yield). Finally, enone

(+) - 27 was transformed to β - hydroxy ketone 29 through epoxidation, followed by reduc-

tion with benzeneselenol generated in situ .

76 Fluorine in Medicinal Chemistry and Chemical Biology

Scheme 3.5 Synthesis of the key intermediate (+) - 29 for (+) - 7b (MGS0028) (1). Reagents

and conditions: (a) ( R,R ) - Trost ligand, allylpalladium chloride dimer, ( n - hex)

4

NBr, NaH,

AcCHFCO

2

Et, CH

2

Cl

2

; (b) 0.1 M, EtONa, EtOH; (c) (i) NBS, acetone, H

2

O, (ii) DBU, CH

2

Cl

2

;

(d) LHMDS, Et

3

Al, THF; (e) IBX, DMSO, PhMe; (f) (i) Br

2

, CH

2

Cl

2

, (ii) ethylene glycol, p -

TsOH - H

2

O, PhMe, (iii) t - BuOK, H

2

O (1 eq.) THF, (iv) 1 M HCl; (v) CH

2

N

2

, (g) (i) TBHP,

Triton B, PhMe, (ii) (PhSe)

2

, NaBH

4

, AcOH, EtOH.

Scheme 3.6 Synthesis of key intermediate (+) - 29 for (+) - 7b (MGS0028) (2). Reagents and

conditions: (a) LDA, NFSI, THF; (b) TBHP, VO(acac)

2

, PhMe; (c) TBSCl, imidazole, DMF;

(d) Et

3

Al, LHMDS; (e) (i) NaClO, RuCl

3

(1 mol%), MeCN, (ii) 1 M HCl.

Next, the most efﬁ cient route to (+) - 7b (MGS0028), to date, via monoprotected ﬂ uo-

rinated diol 43 and ketal 45 as key intermediates is discussed (see Schemes 3.6 and 3.7)

[45] . Key intermediate 43 was synthesized from hydroxycyclopentenylacetate 39 in four

steps: (i) ﬂ uorination of the dianion of 39 (85% yield) to form 40 , (ii) vanadium - mediated

epoxidation of 40 to give epoxide 41 (93% yield), (iii) protection of the hydroxyl moiety

of 41 to form TBS - ether 42 (95% yield), and (iv) cyclopropanation of 42 through ring -

opening of the epoxide moiety to afford key intermediate 43 (96% yield). It should be

noted that the epoxidation of 40 proceeded with excellent stereoselectivity to give the

Fluorinated Conformationally Restricted Glutamate Analogues 77

desired trans - epoxide 41 by exploiting the efﬁ cient directing effect of the free hydroxyl

group. RuCl

3

- mediated oxidation of 43 , followed by desilylation gave (+) - 29 in 95% yield

(see Scheme 3.6 ).

The key intermediate (+) - 29 was converted to the second key intermediate 45 through

ketalization with the bis - O - TMS ester of ( S , S ) - hydrobenzoin to form 44 (quantitative

yield), and the subsequent RuCl

3

- mediated oxidation (93% yield). Strecker reaction of 45

gave aminonitrile 46 with a very good diastereomer ratio (13.1 : 1 by HPLC analysis) as

highly crystalline product. Thus, the desirable diastereomer of 46 was isolated as single

product from the reaction mixture in 80 – 85% yield. Hydrolysis of ketal - aminonitrile 46

proceeded under much milder conditions than those for dithioketal - hydantoin 32 (see

Scheme 4), and (+) - 7b was isolated without utilizing ion - exchange column chromatogra-

phy (94% yield) (see Scheme 3.7 ) [45] . Thus, this optimized process was able to avoid

cumbersome handling, resolution using chiral HPLC and ion - exchange column chroma-

tography, which were included in the original synthesis of (+) - 7b (see Scheme 3.5 ).

3.4.4 Pharmacology and Pharmacokinetics of (+) - 6a ( MGS 0008),

( − ) - 7a ( MGS 0022) and (+) - 7b ( MGS 0028)

3.4.4.1 In vitro Pharmacology of Compounds 6 and 7

The in vitro pharmacological data of ﬂ uorine - containing conformationally restricted

glutamate analogues 6 and 7 are summarized in Table 3.1 [15] . Optically active (+) - 6a

(MGS0008), bearing a ﬂ uorine atom at the C - 3 position of 4 (LY354740), is a potent and

selective agonist for mGluR2/3. Compound (+) - 6a exhibited a high agonist activity for

mGluR2 (EC

50

= 29.4 nM) and mGluR3 (EC

50

= 45.4 nM) as well as a high binding afﬁ nity

to mGluR2 ( K

i

= 47.7 nM) and mGluR3 ( K

i

= 65.9 nM), but did not exhibit signiﬁ cant

Scheme 3.7 Synthesis of (+) - 7b (MGS0028) from key intermediate (+) - 29 . Reagents and

conditions: (a) ( S,S ) - PhCH(OTMS) - CH(OTMS)Ph, TfOH, CH

2

Cl

2

; (b) NaClO, RuCl

3

(0.5 mol%), MeCN; (c) NH

3

/MeOH, Ti(O - Pr - i )

4

, TMSCN; (d) (i) HCl (8 M), AcOH, (ii) H

2

O.

78 Fluorine in Medicinal Chemistry and Chemical Biology

Table 3.1 In vitro and in vivo pharmacological data of m G lu R 2/3 ligands 4 , 6 , 7 and 12

Y

CO

2

R

2

X

3

H

CO

2

H

X

2

NH

2

X

1

Compound X

1

X

2

X

3

Y

Agonist activity

a

Antagonist activity

b

Binding afﬁ nity

c

EC

50

± SEM (nM) IC

50

± SEM (nM) K i ± SEM (nM)

c

mGluR2 mGluR3 mGluR2 mGluR3 mGluR2 mGluR3

4 (LY354740) H H H CH

2

18.3 ± 1.6 62.8 ± 12

– –

23.4 ± 7.1 53.5 ± 13

( ± ) - 6a

F H H CH

2

67.7 ± 9.3

– – – – –

(+) - 6a (MGS0008) F H H CH

2

29.4 ± 3.3 45.4 ± 8.4 > 100 000 > 100 000 47.7 ± 17 65.9 ± 7.1

( − ) - 6a

F H H CH

2

2 640 ± 290

– 36 200 – – –

( ± ) - 6b

H F H CH

2

> 100 000

– 17 100 – – –

( ± ) - 6c

F F H CH

2

> 100 000

– 36 200 – – –

( ± ) - 7a

H H F CH

2

34.2 ± 6.3

– – – – –

(+) - 7a H H F CH

2

1 120 ± 200

– – – – –

( − ) - 7a (MGS0022)

H H F CH

2

16.6 ± 5.6 80.9 ± 31 > 100 000 > 100 000 22.5 ± 7.3 41.7 ± 7.1

( ± ) - 7b

H H F CO

1.26 ± 0.2

– – – – –

(+) - 7b (MGS0028) H H F CO

0.570 ± 0.10 2.07 ± 0.40 > 100 000 > 100 000 3.30 ± 0.31 3.62 ± 1.6

( − ) - 7b

H H F CO

94.7 ± 5.6

– – – – –

( ± ) - 7c

H H Me CH

2

> 100 000

–

> 100 000

– – –

(+) - 12a H OH H CH

2

– – – –

52

d

89

d

( ± ) - 12b

H Me H CH

2

– –

1750 ± 620

e

9830 ± 370

e

983 ± 35

f

146 ± 56

f

– : not determined.

EC

50

: 50% effective concentration.

IC

50

: 50 inhibitory concentration.

K

i

: inhibition constant.

a

Compounds (+) - 6a , ( − ) - 7a and (+) - 7b exhibited no signiﬁ cant agonist activities for rat mGluR1a, mGluR4, mGluR6, and mGluR7 expressed in CHO cells (ED

50

> 100 000 nM).

b

Compounds (+) - 6a , ( − ) - 7a and (+) - 7b exhibited no signiﬁ cant antagonist activities for rat mGluR1a, mGluR4, mGluR6 and mGluR7 expressed in CHO cells (ED

50

> 100 000 nM).

c

Binding afﬁ nities for mGluR2 and mGluR3 were determined by binding study utilizing [

3

H] - MGS0008 in rat mGluR - expressing cells.

d

Displacement of [

3

H]LY354740 binding in rat brain [36] .

e

cAMP responses in human mGluR - expressing cells [37] .

f

Displacement of [

3

H]LY341495 binding to human mGluR - expressing cells [37] .

Fluorinated Conformationally Restricted Glutamate Analogues 79

agonist or antagonist activities for mGluR1a, mGluR4, mGluR5, mGluR6 or mGluR7,

which was similar to compound 4 (LY354740). The agonist activity of (+) - 6a was found

to be highly stereospeciﬁ c, since its enantiomer ( − ) - 6a showed approximately 90 - fold

lower agonist activity (EC

50

= 2,640 nM) than (+) - 6a for mGluR2. Racemic ( ± ) - 6b , dia-

stereomer of ( ± ) - 6a at the C - 3 position, did not exhibit signiﬁ cant agonist (EC

50

> 100 000 nM)

or antagonist (EC

50

= 17 100 nM) activities for mGluR2. The conspicuous difference in

activities between ( ± ) - 6a and ( ± ) - 6b does not seem to be ascribable to the steric effect of

ﬂ uorine incorporation, because mGluR2/3 antagonists 12a (Ro 65 – 3479) or 12b , bearing

a hydroxyl group or a methyl group at the C - 3 α position of 4 , exhibited high or moderate

binding afﬁ nities to mGluR2 ( K

i

= 52 nM or 983 nM) and mGluR3 ( K

i

= 89 nM or 146 nM)

[36, 37] . These results suggest that the decrease in the activity of ( ± ) - 6b for mGluR2 is

due to the large electronegativity of the incorporated ﬂ uorine atom, which inﬂ uences the

electron density of the amino and/or carboxyl groups at the C - 2 position, depending on

its stereochemistry. Similarly, the diﬂ uoro analogue ( ± ) - 6c did not exhibit appreciable

agonist (EC

50

= > 100 000 nM) or antagonist (EC

50

= 36 200 nM) activities for mGluR2.

This lack of activity may be due to the α - ﬂ uorine atom of ( ± ) - 6c , since ( ± ) - 6b with a ﬂ uo-

rine atom at the C - 3 α position exhibited neither agonist nor antagonist activities for

mGluR2, as mentioned above.

Racemic ( ± ) - 7a , bearing a ﬂ uorine at the C - 6 position of ( ± ) - 4 , exhibited a strong

mGluR2 agonist activity (EC

50

= 34.2 nM), which was also found to be highly stereospe-

ciﬁ c. The optically active ( − ) - 7a (MGS0022) exhibited an approximately 67 - fold higher

agonist activity (EC

50

= 16.6 nM) than its enantiomer (+) - 7a (EC

50

= 1 120 nM). Further-

more, compound ( − ) - 7a exhibited a high agonist activity for mGluR3 (EC

50

= 80.9 nM),

but did not for mGluR4, mGluR6, mGluR7, mGluR1a, or mGluR5. No signiﬁ cant antago-

nist activity of ( − ) - 7a was observed for mGluR1a and mGluRs2 – 7. In contrast, ( ± ) - 7c ,

bearing a methyl group at the C - 6 position of ( ± ) - 4 , exhibited neither agonist nor antagonist

activities for mGluR2 (EC

50

> 100 000 nM). The dramatic difference in activity between

( ± ) - 7a and ( ± ) - 7c may be ascribed to the difference in stereoelectronic properties between

ﬂ uorine and a methyl group.

Interestingly, the replacement of the methylene group at the C - 4 position of 7a with

a carbonyl group has substantially enhanced the agonist activity, that is, the resulting

(+) - 7b (MGS0028) is one of the best known agonists for mGluR2/3 to date. Compound

(+) - 7b demonstrated a potent and stereospeciﬁ c agonist activity for mGluR2 (EC

50

= 0.57 nM)

and mGluR3 (EC

50

= 2.07 nM), but neither showed agonistic effect on mGluR1a or

mGluR4 – mGluR7 or antagonistic effect on mGluR1a or mGluR2 – mGluR7. The agonist

activity of (+) - 7b for mGluR2 was approximately 165 - fold higher than that of its enan-

tiomer ( − ) - 7b (EC

50

= 94.7 nM). The greatly enhanced agonist activity of (+) - 7b as com-

pared with ( − ) - 7a may be ascribed to a conformational change caused by the replacement

of the C - 4 methylene moiety to a carbonyl group, especially the relative positions of the

three key functional groups (i.e., one amino group and two carboxylic acids), as well as

the stereoelectronic effects of the carbonyl group introduced.

3.4.4.2 Behavioral Pharmacology of (+) - 6a ( MGS 0008) and (+) - 7b ( MGS 0028)

The antipsychotic - like effects of (+) - 6a (MGS0008) and (+) - 7b (MGS0028) on laboratory

animals are shown in Table 3.2 [15, 51] . It was recently found that phencyclidine

80 Fluorine in Medicinal Chemistry and Chemical Biology

Table 3.2 Antipsychotic - like effects of (+) - 6a ( MGS 0008) and (+) - 7b ( MGS 0028) on

laboratory animals

Y

CO

2

R

2

X

3

H

CO

2

H

X

2

NH

2

X

1

Compound X

1

X

2

X

3

Y PCP - induced

hyperactivity

PCP - induced

head - weaving

behavior

Conditioned

avoidance

ED

50

(mg/kg)

ED

50

( µ g/kg)

ED

50

(mg/kg)

4 (LY354740) H H H CH

2

> 100

3000

> 30

(+) - 6a (MGS0008) F H H CH

2

5.1 260 6.55

(+) - 7b (MGS0028) H H F CO 0.30 0.090 1.67

ED

50

: 50% effective dose.

(PCP) - induced head - weaving behavior in rats was inhibited by the intraperitoneal admin-

istration of 4 (LY354740) [17] . The oral administration of 4 (LY354740) also inhibited

PCP - induced head - weaving behavior (ED

50

= 3.0 mg/kg), but did not affect PCP - induced

hyperactivity (ED

50

> 100 mg/kg) or conditioned avoidance responses (ED

50

> 30 mg/kg)

in rats. In contrast, the oral administration of (+) - 6a (MGS0008) (ED

50

= 0.26 mg/kg)

inhibited PCP - induced head - weaving behavior in rats more effectively (11 - fold) than 4 .

Furthermore, (+) - 6a antagonized PCP - induced hyperactivity (ED

50

= 5.1 mg/kg) and

impaired conditioned avoidance responses (ED

50

= 6.55 mg/kg) in rats. These results indi-

cate that the PCP - induced head - weaving behavior is a sensitive method for screening

mGluR2/3 agonists and the introduction of ﬂ uorine to 4 has clearly increased the oral activ-

ity. It has been reported that the oral bioavailability of 4 in rats is low ( F = 10%), apparently

because of inefﬁ cient drug transfer across the intestinal epithelial membrane [52] . The

enhanced oral activity of (+) - 6 can be attributed to the increase in oral bioavailability and

BBB penetration as a result of the introduction of ﬂ uorine to the drug molecule, which

would enhance lipophilicity as well as bring in unique properties associated with ﬂ uorine.

The oral administration of (+) - 7b (MGS0028) very strongly inhibited PCP - induced

head - weaving behavior in rats (ED

50

= 0.090 µ g/kg), that is, (+) - 7b was much more effec-

tive than 4 (LY354740) and (+) - 6a (MGS0008). Furthermore, the oral administration of

(+) - 7b strongly antagonized PCP - induced hyperactivity in rats (ED

50

= 0.30 mg/kg) and

impaired the conditioned avoidance responses (ED

50

= 1.67 mg/kg) in rats. Excellent anti-

psychotic - like effects of (+) - 6a (MGS0008) and (+) - 7b (MGS0028) as mGluR2/3 agonists

are very encouraging for their potential use in the treatment of schizophrenia.

3.4.4.3 Pharmacokinetics of (+) - 7b ( MGS 0028)

The metabolism and disposition of (+) - 7b (MGS0028) in three preclinical species (rats,

dogs, and monkeys) are summarized in Table 3.3 [53] . In rats, (+) - 7b (MGS0028) was

Fluorinated Conformationally Restricted Glutamate Analogues 81

Table 3.3 Pharmacokinetic parameters of (+) - 7b ( MGS 0028) in Sprague - Dawley rats, rhesus monkeys, and beagle dogs

Parameter

a

Sprague - Dawley rats Rhesus monkeys Beagle dogs

3 mg/kg i.v. 1 mg/kg p.o. 10 mg/kg p.o. 1 mg/kg i.v. 5 mg/kg p.o. 0.3 mg/kg i.v. 0.1 mg/kg p.o. 0.3 mg/kg p.o.

C

max

( µ M)

NA

b

1.0 ± 0.2 6.0 ± 1.9

NA

b

1.0 ± 0.5

NA

b

1.5 ± 0.8 4.0 ± 1.0

t

max

(h) NA

b

0.8 ± 0.2 3.0 ± 1.4

NA

b

2.3 ± 1.5

NA

b

0.4 ± 0.1 0.5 ± 0.0

AUC

0 – 24 h

( µ M h) 14.3 ± 0.8 3.4 ± 0.5 35.8 ± 3.8 10.2 ± 2.6 10.4 ± 5.0 8.2 ± 1.1 1.7 ± 0.9 5.7 ± 0.3

Effective t

1/2

(h)

1.1

NA

b

NA

b

1.1

NA

b

0.9

NA

b

NA

b

CL

p

(ml/min/kg)

16.2 ± 0.9

NA

b

NA

b

8.0 ± 1.8

NA

b

2.8 ± 0.4

NA

b

NA

b

V

d

(L/kg)

0.5 ± 0.2

NA

b

NA

b

0.6 ± 0.1

NA

b

0.1 ± 0.01

NA

b

NA

b

F (%) NA

b

70.7 75.3

NA

b

20.3

c

NA

b

63.4 69

AUC

Metabolite

/AUC

parent

0.8 0.4 0.3 0.3 0.9 0.0 0.0 0.0

a

C

max

: maximum plasma or tissue concentration, t

max

: time to reach maximum plasma concentration, AUC

0 – 24

: area under the concentration – time curve from time 0 to 24 hours,

Effective t

1/2

: effective elimination half - life, CL

p

: plasma clearance, V

d

: volume of distribution, F : bioavailability.

b

Not applicable.

c

Some monkeys experienced emesis, and this may be partially responsible for low bioavailability.

Ojima I. (ed.) Fluorine in Medicinal Chemistry and Chemical Biology

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