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

62 Fluorine in Medicinal Chemistry and Chemical Biology

dinor - AFP - 172, and 1,2,3,4 - tetranor - AFP - 172, accounted for most of the radioactivity in

the aqueous humor and other ocular tissues. AFP - 172 was demonstrated to be the most

abundant and the only pharmacologically active metabolite in ocular tissues. A small

amount of taﬂ uprost was detected in the ciliary body, cornea, and iris.

2.4 Conclusion

A novel 15,15 - diﬂ uorinated prostanoid, taﬂ uprost was discovered as a highly potent and

selective prostanoid FP receptor agonist. Taﬂ uprost demonstrates powerful and prolonged

IOP - lowering effects in animal models. The maximal IOP reduction achieved with taﬂ u-

prost was greater than that with latanoprost in both normotensive and glaucomatous

monkeys. Taﬂ uprost showed signiﬁ cantly increasing efﬁ cacy of ocular blood ﬂ ow and

protective effect on glutamate - induced cytotoxicity. In its pharmacological characteristics,

taﬂ uprost may be superior to latanoprost: potent IOP - reducing efﬁ cacy, effective increase

in ocular blood ﬂ ow, and weak melanogenetic side - effect. Taﬂ uprost has completed clini-

cal trials, and new drug applications for taﬂ uprost have been ﬁ led in Japan and the EU.

Taﬂ uprost is expected to become a new - generation prostanoid FP agonist that strongly

reduces IOP and effectively improves ocular circulation in patients with glaucoma.

Acknowledgments

The author thanks the collaborators at Research & Development Center, Santen Pharma-

ceutical Co., Ltd. for pharmacological studies and fruitful discussions in the development

of taﬂ uprost. The author is also grateful to coworkers at Asahi Glass Co., Ltd. whose names

are shown in published papers for their essential contributions.

References

Vane , J. R. and O ’ Grady , J. ( 1993 ) Therapeutic Applications of Prostaglandins , Edward Arnold ,

London .

Coleman , R. A. , Kennedy , I. , Humphery , P. P. A. , et al. ( 1990 ) Prostanoids and their receptors .

In: Comprehensive Medicinal Chemistry , vol. 3 (ed. J. C. Emmett ) – , Pergamon , Oxford , pp.

643 – 714 .

(a) Coleman , R. A. , Smith , W. L. and Narumiya , S. ( 1994 ) Classiﬁ cation of prostanoid receptors:

Properties, distribution, and structure of the receptors and their subtypes . Pharmacological

Reviews , 46 , 205 – 229 ; (b) Narumiya , S. , Sugimoto , Y. and Ushikubi , F. ( 1999 ) Prostanoid

receptors: Structures, properties, and functions . Physiological Reviews , 79 , 1193 – 1226 ; (c) Hata ,

A. N. and Breyer , R. M. ( 2004 ) Pharmacology and signaling of prostaglandin receptors: Multiple

roles in inﬂ ammation and immune modulation . Pharmacology & Therapeutics , 103 , 147 – 166 ;

(d) Murota , S. and Yamamoto , S. ( 2001 ) New Development of Prostaglandin Research , vol. 38 ,

Tokyo Kagaku Dojin , Tokyo .

1.

2.

3.

Fluorinated Prostanoids 63

[A second PGD

2

receptor having different functions, chemoattractant receptor - homologous

molecule expressed on T helper (Th) 2 cells (CRTH2), was also identiﬁ ed recently.] (a) Hirai ,

H. , Tanaka , K. , Yoshie , et al. ( 2001 ) Prostaglandin D

2

selectively induces chemotaxis in T helper

type 2 cells, eosinophils, and basophils via seven - transmembrane receptor CRTH2 . Journal of

Experimental Medicine , 193 , 255 – 261 ; (b) Nagata , K. , Tanaka , K. , Ogawa , K. , et al. ( 1999 )

Selective expression of a novel surface molecule by human Th2 cells in vivo . Journal of Immu-

nology , 162 , 1278 – 1286 .

(a) Woodward , D. F. , Regan , J. W. , Lake , S. and Ocklind , A. ( 1997 ) Molecular biology and

ocular distribution of prostanoid receptors . Survey of Ophthalmology. , 41 Suppl 2 , S 15 – 21 ;

(b) Ocklind , A. , Lake , S. , Wentzel , P. , et al. ( 1996 ) Localization of the prostaglandin F2 alpha

receptor messenger RNA and protein in the cynomolgus monkey eye . Investigative Ophthalmol-

ogy & Visual Science , 37 , 716 – 726 .

(a) Schl ö tzer - Schrehardt , U. , Zenkel , M. and N ü sing , R. M. ( 2002 ) Expression and localization

of FP and EP prostanoid receptor subtypes in human ocular tissues . Investigative Ophthalmology

& Visual Science , 43 , 1475 – 1487 ; (b) Anthony , T. L. , Pierce , K. L. , Stamer , W. D. and Regan ,

J. W. ( 1998 ) Prostaglandin F

2 α

receptors in the human trabecular meshwork . Investigative Oph-

thalmology & Visual Science , 39 : 315 – 321 ; (c) Mukhopadhyay , P. , Bian , L. , Yin , H. , et al. ( 2001 )

Localization of EP

1

and FP receptors in human ocular tissues by in situ hybridization . Investiga-

tive Ophthalmology & Visual Science , 42 : 424 – 428 .

Kamphuis , W. , Schneemann , A. van Beek , L. M. , et al. ( 2001 ) Prostanoid receptor gene expres-

sion proﬁ le in human trabecular meshwork: A quantitative real - time PCR approach . Investiga-

tive Ophthalmology & Visual Science , 42 , 3209 – 3215 .

(a) Filler , R. and Kobayashi , Y. ( 1982 ) Biomedicinal Aspects of Fluorine Chemistry , Kodansya

and Elsevier Biomedical , Tokyo and Amsterdam ; (b) Welch , J. T. and Eswarakrishman , S. ( 1991 )

Fluorine in Bioorganic Chemistry , John Wiley & Sons , New York ; (c) Filler , R. , Kobayashi , Y.

and Yagupolskii , L. M. ( 1993 ) Organoﬂ uorine Compounds in Medicinal Chemistry and Bio-

medical Applications , Elsevier , Amsterdam ; (d) Kukhar , V. P. and Soloshonok , V. A. ( 1995 )

Fluorine - containing Amino Acids: Synthesis and Properties , John Wiley & Sons Ltd , Chiches-

ter ; (e) Ojima , I. , McCarthy , J. R. and Welch , J. T. ( 1996 ) Biomedical Frontiers of Fluorine

Chemistry , American Chemical Society , Washington, D.C. ; (f) Hiyama , T. ( 2000 ) Organoﬂ uo-

rine Compounds, Chemistry and Applications , Springer , Berlin ; (g) Kirsch , P. ( 2004 ) Modern

Fluoroorganic Chemistry , Wiley - VCH Verlag GmbH , Weinheim ; (h) Uneyama , K. ( 2006 )

Organoﬂ uorine Chemistry , Blackwell , Oxford ; (i) Begue , J - P. and Bonnet - Delpon , D. ( 2006 )

Recent advances (1995 – 2005) in ﬂ uorinated pharmaceuticals based on natural products . Journal

of Fluorine Chemistry , 127 , 992 – 1012 ; (j) Kirk , K. L. ( 2006 ) Fluorine in medicinal chemistry:

Recent therapeutic applications of ﬂ uorinated small molecules . Journal of Fluorine Chemistry ,

127 , 1013 – 1029 .

(a) Roberts , S. M. and Scheimann , F. ( 1982 ) New Synthetic Routes to Prostaglandins

and Thromboxanes , Academic Press , London ; (b) Collins , P. W. and Djuric , S. W. ( 1993 )

Synthesis of therapeutically useful prostaglandin and prostacyclin analogs . Chemical Reviews ,

93 , 1533 – 1564 ; (c) Das , S. , Chandrasekhar , S. , Yadav , J. S. and Gr é e , R. ( 2007 ) Recent

developments in the synthesis of prostaglandins and analogues . Chemical Reviews , 107 ,

3286 – 3337 .

(a) Barnette , W. E. ( 1984 ) The synthesis and biology of ﬂ uorinated prostacyclins . CRC Critical

Rev. Biochem. , 15 , 201 – 235 ; (b) Yasuda , A. The ﬂ uoroarachidonic acid cascade , in Ref [8c] ,

pp. 275 – 307 ; (c) Matsumura , Y. ( 2005 ) Recent developments in ﬂ uorinated prostanoids Journal

of Synthetic Organic Chemistry, Japan , 63 , 40 – 50 ; (d) Matsumura , Y. ( 2008 ) Synthesis and

pharmacological properties of ﬂ uorinated prostanoids , in Fluorine and Health: Molecular

Imaging, Biomedical Materials and Pharmaceuticals (eds A. Tressaud and G. Haufe ), Elsevier ,

Amsterdam , pp. 623 – 659 .

4.

5.

6.

7.

8.

9.

10.

64 Fluorine in Medicinal Chemistry and Chemical Biology

Dukes , M. , Russel , W. and Walpole , A. L. ( 1974 ) Potent luteolytic agents related to prostaglan-

din F

2 α

Nature , 250 , 330 – 331 .

Magerlein , B. J. and Miller , W. L. ( 1975 ) 16 - Fluoroprostaglandins . Prostaglandins , 9 ,

527 – 530 .

Fried , J. , Mitra , M. , Nagarajan , M. and Mehrotra , M. M. ( 1980 ) 10,10 - Diﬂ uoro - 13 - dehydro-

prostacyclin: a chemically and metabolically stabilized potent prostacyclin . Journal of Medici-

nal Chemistry , 23 , 234 – 237 .

(a) Morinelli , T. A. , Okwu , A. K. , Mais , et al. ( 1989 ) Diﬂ uorothromboxane A2 and stereoiso-

mers: stable derivatives of thromboxane A2 with differential effects on platelets and blood

vessels . Proceedings of the National Academy of Sciences of the USA , 86 , 5600 – 5604 ; (b) Fried ,

J. , John , V. , Szwedo , M. J. , et al. ( 1989 ) Synthesis of 10,10 - diﬂ uorothromboxane A2, a potent

and chemically stable thromboxane agonist . Journal of the American Chemical Society , 111 ,

4510 – 4511 .

(a) Nakano , T. , Makino , M. , Morizawa , Y. and Matsumura , Y. ( 1996 ) Synthesis of novel diﬂ uo-

roprostacyclin derivatives: unprecedented stabilizing effect of ﬂ uorine substituents . Angewandte

Chemie, International Edition English , 35 , 1019 – 1021 ; (b) Matsumura , Y. , Nakano , T. , Mori ,

N. and Morizawa , Y. ( 2004 ) Synthesis and biological properties of novel ﬂ uoroprostaglandin

derivatives: highly selective and potent agonists for prostaglandin receptors . Chimia , 58 , 148 –

152 ; (c) Matsumura , Y. , Nakano , T. , Asai , T. and Morizawa , Y. Synthesis and properties of novel

ﬂ uoroprostacyclins. Potent and stable prostacyclin agonists , in Ref. [8e] , pp. 83 – 94 .

Chan , C - S. , Negishi , M. , Nakano , T. , et al. ( 1997 ) 7,7 - Diﬂ uoroprostacyclin derivative, AFP - 07,

a highly selective and potent agonist for the prostacyclin receptor . Prostaglandins , 53 , 83 – 90 .

(a) Iwase , A. , Suzuki , Y. , Araie , M. , et al. ( 2004 ) The prevalence of primary open - angle glau-

coma in Japanese. 1. The Tajimi Study . Ophthalmology , 111 , 1641 – 1648 ; (b) Yamamoto , T. ,

Iwase , A. , Araie , M. , et al. ( 2005 ) The Tajimi Study report 2: prevalence of primary angle closure

and secondary glaucoma in a Japanese population . Ophthalmology , 112 , 1661 – 1669 .

Collaborative Normal - Tension Glaucoma Study Group , ( 1998 ) Comparison of glaucomatous

progression between untreated patients with normal - tension glaucoma and patients with thera-

peutically reduced intraocular pressures . American Journal of Ophthalmology . 126 , 487 – 497 .

(a) Camras , C. B. and Bito , L. Z. ( 1981 ) Reduction of intraocular pressure in normal and glau-

comatous primate ( Aotus trivirgatus ) eyes by topically applied prostaglandin F

2 α

. Current Eye

Research , 1 , 205 – 209 ; (b) Bito , L. Z. ( 1984 ) Comparison of the ocular hypotensive efﬁ cacy of

eicosanoids and related compounds . Experimental Eye Research , 40 , 181 – 194 .

(a) Stjernschantz , J. and Resul , B. ( 1992 ) Phenyl substituted prostaglandin analogs for glaucoma

treatment . Drugs of the Future , 17 , 691 – 704 ; (b) Ishida , N. , Odani - Kawabata , N. , Shiazaki , A.

and Hara , H. ( 2006 ) Prostanoids in the therapy of glaucoma . Cardiovascular Drug Reviews , 24 ,

1 – 10 .

Sakurai , M. , Araie , M. , Oshika , T. , et al. ( 1991 ) Effects of topical application of UF - 021, a novel

prostaglandin derivative, on aqueous humor dynamics in normal human eyes . Japanese Journal

of Ophthalmology ., 35 , 156 – 165 .

Resul , B. , Stjernschantz , J. , No , K. , et al. ( 1993 ) Phenyl - substituted prostaglandins: Potent and

selective antiglaucoma agents . Journal of Medicinal Chemistry , 36 , 243 – 248 .

(a) Wand , M. , Ritch , R. , Isbey , E. K. J. and Zimmerman , T. J. ( 2001 ) Latanoprost and periocular

skin color changes . Archives of Ophthalmology , 119 , 614 – 615 ; (b) Woodward , D. F. , Krauss ,

A. H. , Chen , J. , et al. ( 2003 ) Pharmacological characterization of a novel antiglaucoma agent,

bimatoprost (AGN 192024) . The Journal of Pharmacology and Experimental Therapeutics 305 ,

772 – 785 .

(a) Netland , P. A. , Landry , T. , Sullilvan , E. K. , et al. ( 2001 ) Travoprost compared with latano-

prost and timolol in patients with open - angle glaucoma or ocular hypertension . American

Journal of Ophthalmology , 132 , 472 – 484 ; (b) Hellberg , M. R. , Sallee , V. L. , Mclaughlin , M.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

Fluorinated Prostanoids 65

A. , et al. ( 2001 ) Preclinical efﬁ cacy of travoprost, a potent and selective FP prostaglandin recep-

tor agonist . Journal of Ocular Pharmacology & therapeutics 17 , 421 – 432 .

Boulton , L. T. , Brick , D. , Fox , M. E. , et al. ( 2002 ) Synthesis of the potent antiglaucoma agent,

travoprost . Organic Process Research & Development , 6 , 138 – 145 .

(a) Gabelt , B. T. and Kaufman , P. L. ( 1989 ) Prostaglandin F

2 α

increases uveoscleral outﬂ ow in

the cynomolgus monkey . Experimental Eye Res 49 , 389 – 402 ; (b) Stjernschantz , J. , Sel é n , G. ,

Sj ö quist , B. and Resul , B. ( 1995 ) Preclinical pharmacology of latanoprost, a phenyl - substituted

PGF

2 α

analogue . Advances in Prostaglandin, Thromboxane, and Leukotriene Research , 23 ,

513 – 518 .

(a) Wand , M. , Ritch , R. , Isbey , E. K. J. and Zimmerman , T. J. ( 2001 ) Latanoprost and periocular

skin color changes . ArchIves of Ophthalmology , 119 , 614 – 615 ; (b) Alexander , C. L. , Miller ,

S. J. and Abel , S. R. ( 2002 ) Prostaglandin analog treatment of glaucoma and ocular hyperten-

sion . Annals of Pharmacotherapy , 36 , 504 – 511 .

Takasuka , M. , Kishi , M. and Yamakawa , M. ( 1994 ) FTIR spectral study of intramolecular

hydrogen bonding in thromboxane A2 receptor agonist (U - 46619), prostaglandin (PG)E

2

, PGD

2

,

PGF

2 α

, prostacyclin receptor agonist (carbacyclin) and their related compounds in dilute carbon

tetrachloride solution: structure - activity relationships . Journal of Medicinal Chemistry , 37 ,

47 – 56 .

[A report of PGF derivatives on ligand docking experiments to a human FP receptor model]

Wang , Y. , Wos , J. A. , Dirr , M. J. , et al. ( 2000 ) Design and synthesis of 13,14 - dihydro prosta-

glandin F

1 α

analogues as potent and selective ligands for the human FP receptor . Journal of

Medicinal Chemistry , 43 , 945 – 952 .

(a) [Synthesis of 15 - deoxy - 15 - ﬂ uoro - PGF

2 α

] Bezuglov , V. V. and Bergelson , L. D. ( 1980 ) Syn-

thesis of ﬂ uoroprostacyclins . Doklady Akademii Nauk SSSR , 250 , 468 – 469 ; (b) [Recently, the

ocular hypotensive effects of 15 - deoxy - 15 - ﬂ uoro - PGF

2 α

derivatives have been independently

reported] Klimko , P. , Hellberg , M. , McLaughlin , M. , et al. ( 2004 ) 15 - Fluoro prostaglandin FP

agonists: a new class of topical ocular hypotensives . Bioorg. Med. Chem. , 12 , 3451 – 3469 .

Resul , B. and Stjernschantz , J. ( 1993 ) Structure - activity relationships of prostaglandin analogues

as ocular hypotensive agents . Expert Opinion on Therapeutic Patents , 3 , 781 – 795 .

(a) Howard , J. A. K. , Hoy , V. J. , O ’ Hagen , D. and Smith , G. T. ( 1996 ) How good is ﬂ uorine as

a hydrogen bond acceptor? Tetrahedron , 52 , 12613 – 12622 ; (b) Dunitz , J. D. and Taylor , R.

( 1997 ) Organic ﬂ uorine hardly ever accepts hydrogen bonds . Chemistry A European Journal ,

3 , 89 – 98 ; (c) Ref. [8h] , Chapter 4.

Matsumura , Y. , Mori , N. , Nakano , T. , et al. ( 2004 ) Synthesis of the highly potent prostanoid FP

receptor agonist, AFP - 168: a novel 15 - deoxy - 15,15 - diﬂ uoroprostaglandin F

2 α

derivative . Tetra-

hedron Letters , 45 , 1527 – 1529 .

Nakajima , T. , Matsugi , T. , Goto , W. , et al. ( 2003 ) New ﬂ uoroprostaglandin F

2 α

derivatives with

prostanoid FP - receptor agonistic activity as potent ocular - hypotensive agents . Biological &

Pharmaceutical Bulletin , 26 , 1691 – 1695 .

Takagi , Y. , Nakajima , T. , Shimazaki , A. , et al. ( 2004 ) Pharmacological characteristics of AFP -

168 (taﬂ uprost), a new prostanoid FP receptor agonist, as an ocular hypotensive drug . Experi-

mental; Eye Research , 78 , 767 – 776 .

Sharif , N. A. , Kelly , C. R. , Crider , J. Y. , et al. ( 2003 ) Ocular hypotensive FP prostaglandin (PG)

analogs: PG receptor subtype binding afﬁ nities and selectivities, and agonist potencies at FP

and other PG receptors in cultured cells . Journal of Ocular Pharmacology & Therapeutics 19 ,

501 – 515 .

(a) Brubaker , R. F. , Schoff , E. O. , Nau , C. B. , et al. ( 2001 ) Effects of AGN 192024, a new ocular

hypotensive agent, on aqueous dynamics . American Journal of Ophthalmology 131 , 19 – 24 ; (b)

Brubaker , R. F. , Schoff , E. O. , Nau , C. B. , et al. ( 2005 ) Effects of travoprost on aqueous humor

dynamics in monkeys . Journal of Glaucoma , 14 , 70 – 73 .

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

66 Fluorine in Medicinal Chemistry and Chemical Biology

Ota , T. , Murata , H. , Sugimoto , E. , et al. ( 2005 ) Prostaglandin analogues and mouse intraocular

pressure: effects of taﬂ uprost, latanoprost, travoprost, and unoprostone, considering 24 - hour

variation . Investigative Ophthalmology & Visual Science . 46 , 2006 – 2011 .

Ota , T. , Aihara , M. , Saeki , T. , et al. ( 2007 ) The IOP - lowering effects and mechanism of action

of taﬂ uprost in prostanoid receptor - deﬁ cient mice . British Journal of Ophthalmolology 91 ,

673 – 676 .

(a) Ota , T. , Aihara , M. , Narumiya , S. and Araie , M. ( 2005 ) The effects of prostaglandin ana-

logues on IOP in prostanoid FP - receptor - deﬁ cient mice . Investigative Ophthalmology & Visual

Science . 46 , 4159 – 4163 ; (b) Ota , T. , Aihara , M. , Saeki , T. , et al. ( 2006 ) The effects of prosta-

glandin analogues on prostanoid EP1, EP2, and EP3 receptor - deﬁ cient mice . Investigative

Ophthalmology & Visual Science . 47 , 3395 – 3399 .

Izumi , N. , Nagaoka , T. , Sato , E. , et al. ( 2004 ) DE – 085 increases retinal blood ﬂ ow . Investigative

Ophthalmology & Visual Science . 45 , Abst. 2340 .

Akaishi , T. , Kurashima , H. , Odani , N. , et al. ( 2007 ) Comparison of the effects of taﬂ uprost,

latanoprost and travoprost on the optic nerve head blood ﬂ ow in rabbits . Investigative Ophthal-

mology & Visual Science . 48 , Abst. 2278 .

Odani , N. , Seike , H. , Kurashima , H. , et al. ( 2007 ) Protective effect of taﬂ uprost on glutamate -

induced cytotoxicity . World Glaucoma Congress , Singapore, 2007, Geneva Medical publishers ,

Geneva , Abst. P327, p. 184 .

Ferrer , E. and Bozzo , J. ( 2006 ) Understanding optic nerve degradation: key to neuroprotection

inglaucoma . Drugs of the Future , 31 , 355 – 363 .

Bergh , K. , Wentzel , P. and Stjernschantz , J. ( 2002 ) Production of prostaglandin E

2

by iridial

melanocytes exposed to latanoprost acid, a prostaglandin F

2 α

analogue . Journal of Ocular

Pharmacology & therapeutics , 18 , 391 – 400 .

Kawazu , K. and Fukano , Y. ( 2006 ) Distribution and metabolism of [

3

H]taﬂ uprost in ocular

tissues following administration of a single ocular dose to Cynomolgus monkey . Investigative

Ophthalmology & Visual Science . 47 , Abst. 5102 .

38.

39.

40.

41.

42.

43.

44.

45.

46.

3

Fluorinated Conformationally Restricted

Glutamate Analogues for CNS Drug

Discovery and Development

Atsuro Nakazato

3.1 Introduction

(1 S ,2 R ,5 R ,6 S ) - 2 - Aminobicyclo[3.1.0]hexane - 2,6 - dicarboxylic acid ( 4 ; see Figure 3.2 ),

a conformationally restricted glutamate analogue, is a selective group II metabotropic

glutamate receptor (mGluR2/3) agonist. Orally active mGluR2/3 agonists and antagonists

have been successfully discovered by the introduction of ﬂ uorine atoms onto the

bicyclo[3.1.0]hexane ring of 4 . (1 S ,2 S ,3 S ,5 R ,6 S ) - 2 - Amino - 3 - ﬂ uorobicyclo[3.1.0]hexane -

2,6 - dicarboxylic acid ((+) - 6a , MGS0008), (1 R ,2 S ,5 R ,6 R ) - 2 - amino - 6 - ﬂ uorobicyclo[3.1.0]

hexane - 2,6 - dicarboxylic acid (( − ) - 7a , MGS0022) and (1 R ,2 S ,5 S ,6 S ) - 2 - amino - 6 - ﬂ uoro - 4 -

oxobicyclo[3.1.0]hexane - 2,6 - dicarboxylic acid monohydrate ((+) - 7b , MGS0028) are

typical ﬂ uorinated mGluR2/3 agonists. Among these agonists, the orally administered

compounds (+) - 6a (MGS0008) and (+) - 7b (MGS0028), in particular, show potent anti-

psychotic - like effects in laboratory animals. (1 R ,2 R ,3 R ,5 R ,6 R ) - 2 - Amino - 3 - (3,4 - dichloro-

benzyloxy) - 6 - ﬂ uorobicyclo[3.1.0]hexane - 2,6 - dicarboxylic acid ( 14a , MGS0039) is a

typical ﬂ uorinated mGluR2/3 antagonist, and its n - heptyl 6 - carboxylate 15a , a compound

that was designed by utilizing the chemical characteristics of α - ﬂ uoro carboxylic acid, is

the most effective prodrug for 14a (MGS0039).

In this chapter, the design strategy, synthesis, pharmacology, and pharmacokinetics

of ﬂ uorinated conformationally restricted glutamate analogues are described in compari-

son with those of the corresponding hydrocarbon - based compounds.

Fluorine in Medicinal Chemistry and Chemical Biology Edited by Iwao Ojima

68 Fluorine in Medicinal Chemistry and Chemical Biology

3.2 Metabotropic Glutamate Receptors

l - Glutamate ( 2 ) acts as a neurotransmitter at the vast majority of excitatory synapses in

the brain. The normal functioning of glutamatergic synapses is required for all major brain

functions [1, 2] . Glutamate receptors are broadly classiﬁ ed into two types: ionotropic

glutamate receptors (iGluRs), in which the receptors have an ion channel structure, and

metabotropic glutamate receptors (mGluRs), which are coupled to G - proteins. mGluRs

are classiﬁ ed into eight subtypes, identiﬁ ed as subtypes 1 through 8, which are further

classiﬁ ed into three groups (I – III) on the basis of sequence homology, signal transduction

mechanisms, and pharmacology [3 – 9] . Group I mGluRs (mGluR1/5) are positively coupled

to phospholipase C, and their activation produces phosphoinositide turnover and diacylg-

lycerol within target neurons. In contrast, both group II mGluRs (mGluR2/3) and group

III mGluRs (mGluR4/6/7/8) are located in glutamatergic terminals and are negatively

coupled to the activity of adenyl cyclase (see Figure 3.1 ) [9 – 11] .

mGluRs have been implicated in the pathology of major psychiatric disorders such

as depression, anxiety, and schizophrenia [12] because of their critical role as modulators

of synaptic transmission, ion channel activity, and synaptic plasticity [7] . Indeed, the efﬁ -

cacy of mGluR2/3 agonists in animal models and in clinical trials suggests that, by inhibit-

ing the glutamatergic system, agonists of mGluR2/3 may be useful for the treatment of

many diseases and conditions including schizophrenia [3 – 17] , anxiety [13, 14, 18 – 21] ,

and panic disorder [22] .

In contrast, clariﬁ cation of the efﬁ cacy of mGluR2/3 antagonists in animal models

has taken longer than that of mGluR2/3 agonists. This delay might be due to the lack

of potent and selective mGluR2/3 antagonists capable of penetrating the blood – brain

barrier (BBB). The antidepressant - like and anxiolytic effects of mGluR2/3 antagonists,

14a (MGS0039) [23 – 31] and (2 S ) - amino - 2 - [(1 S ,2 S ) - 2 - carboxycycloprop - 1 - yl] - 3 - (9 -

xanthyl)propionic acid ( 11 , LY341495) [32, 33] , have been reported. Compound 14a

(MGS0039) exerted dose - dependent antidepressant - like effects in the rat forced - swim test

Ionotropic glutamate receptors (iGluRs)

- NMDA

- AMPA

- Kainate

- Group I

- Group II

- Group III

- Positively coupled to phospholipase C

- Located in glutamatergic terminals

- Negatively coupled to the activity of

adenyl cyclase

Metabotropic glutamate receptors (mGluRs)

mGluR1

mGluR5

mGluR2

mGluR3

mGluR4

mGluR6

mGluR7

mGluR8

Figure 3.1 Glutamate receptors (GluRs).

Fluorinated Conformationally Restricted Glutamate Analogues 69

and the mouse tail suspension test, but had no apparent effects on classical models of

anxiety, such as the rat social interaction test and the rat elevated plus - maze (0.3 – 3 mg/kg,

i.p.). However, compound 14a (MGS0039) showed dose - dependent anxiolytic - like

activities when evaluated using the conditioned fear stress test in rats, the marble - burying

behavior test in mice, and the stress - induced hyperthermia test in single housed mice.

These ﬁ ndings suggest that mGluR2/3 antagonists may be useful for the treatment of

depression and anxiety.

3.3 m G lu R 2/3 Agonists and Antagonists

Typical mGluR2/3 antagonists that have been derived from the corresponding agonists are

shown in Figure 3.2 . The 2 - methyl analogue ( 8 , MAP - 4) of agonist 1 is a weak but selec-

tive antagonist for group III mGluRs [34] . A potent and relatively selective antagonist for

mGluR2/3, compound 9 , was obtained by introducing a 4,4 - diphenybutyl group at the C - 4

position of glutamic acid ( 2 ). Furthermore, the introduction of a phenyl group to the C - 2 ′

position of 3 or a 9 - xanthylmethyl group at the C - 2 position of 3 yielded moderately potent

and very potent mGluR2/3 antagonists 10 [35] and 11 (LY341495) [32, 33] , respectively.

Compound 11 (LY341495) binds to rat brain mGluRs with a very high afﬁ nity

(IC

50

= 2.9 nM) and is a very potent functional antagonist (IC

50

= 23 nM and 10 nM for

human mGluR2 and mGluR3, respectively). Additionally, the intraperitoneal administra-

tion of 11 (LY341495) resulted in good plasma and acceptable brain concentrations, but

the oral bioavailability of 11 (LY341495) was low ( < 5%) [33] . A selective mGluR2/3

agonist 4 (LY354740) exhibits oral activity [21] and has been chemically modiﬁ ed to dis-

cover better drug candidates. Among these compounds, compound 5 (LY404039) is a

typical agonist for mGlu2/3 receptors with a good pharmacokinetic proﬁ le in laboratory

animals [14] . In contrast, the introduction of a hydroxyl group or a methyl group at the

C - 3 position of a typical group II mGluR agonist 4 (LY354740) yielded mGluR2/3 antago-

nists 12a (Ro 65 – 3479) [36] and 12b [37] , respectively.

On the basis of the chemical properties of ﬂ uorine, the introduction of a ﬂ uorine atom

into compound 4 (LY354740) was an interesting endeavor, resulting in compounds 6 and

7 . Fluorine is not a sterically demanding substituent, since its small van der Waals radius

resembles that of hydrogen. In molecules where conformational recognition is important,

minimal steric disturbance by a substituent is especially critical. The electronegativity of

ﬂ uorine can have pronounced effects on the electron density within molecules, affecting

the basicity or acidity of neighboring groups, dipole moments within molecules, and the

overall reactivity and stability of neighboring functional groups. Once introduced, the high

carbon – ﬂ uorine bond energy renders the substituent relatively resistant to metabolic trans-

formation [38] . Given the nature of ﬂ uorine, the C - 3 or C - 6 position of the conformation-

ally restricted glutamate analogue 4 (LY354740) – an orally active, potent, and selective

mGluR2/3 agonist – was selected for the introduction of ﬂ uorine, since its introduction

was expected to inﬂ uence the functional groups (carboxylic acid and the amino group

at the C - 2 position or the carboxylic acid at the C - 6 position) in a direct manner.

Fluoro - compounds 6a (MGS0008) and 7a (MGS0022) exhibited the best inhibitory effects

on cAMP formation, with the same EC

50

values as that of compound 4 (LY354740). In

70 Fluorine in Medicinal Chemistry and Chemical Biology

Figure 3.2 Group II mGluR agonists and antagonists.

addition, 6a (MGS0008) had a higher oral activity in laboratory animals than compound

4 (LY354740) [15] . Moreover, chemical modiﬁ cation based on the replacement of the CH

2

group at the C - 4 position of compound ( − ) - 7a (MGS0022) with a carbonyl group produced

(+) - 7b (MGS0028), which displayed the best mGluR2/3 agonist properties in both in vitro

and in vivo pharmacological proﬁ les [15] . In contrast, the introduction of an alkoxy group

at the C - 3 position of ( − ) - 7a (MGS0022) yielded a potent and selective mGluR2/3 anta-

gonist, 14a (MGS0039) [25] . The antagonist 14a (MGS0039) showed acceptable BBB

penetration, and its low oral bioavailability in laboratory animals has been improved by

Fluorinated Conformationally Restricted Glutamate Analogues 71

the discovery of prodrug 15a (MGS0210), which was designed by applying the charac-

teristics of α - ﬂ uoro carboxylic acid [39, 40] .

3.4 m G lu R 2/3 Agonists (+) - 6a ( MGS 0008), ( − ) - 7a ( MGS 0022),

and (+) - 7b ( MGS 0028)

In this section, the original syntheses and pharmacological proﬁ les of racemic and optically

active compounds 6a , 6b , 6c , 7a, and 7b are presented [15] . The process chemistry for

(+) - 6a (MGS0008) [41] and (+) - 7b (MGS0028) [42 – 45] is also described. Structures in

the following schemes illustrate the absolute conﬁ gurations corresponding to (+) - 6a

(MGS0008) and (+) - 7b (MGS0028) for simplicity, Thus, only one structure is shown for

racemic compounds and the structures of enantiomers corresponding to ( − ) - 6a and ( − ) - 7b

are not depicted.

3.4.1 Synthesis of (+) - 6a ( MGS 0008)

Racemic compounds ( ± ) - 6a , ( ± ) - 6b , and ( ± ) - 6c , and optically pure compounds (+) - 6a

(MGS0008) and ( − ) - 6a , were originally synthesized via racemic ﬂ uorinated intermediates,

( ± ) - 17a - 1 , ( ± ) - 17b , and ( ± ) - 17c , respectively, which were synthesized by the ﬂ uorination

of the racemic compound ( ± ) - 16 (see Scheme 3.1 ) [15] .

Racemic compound ( ± ) - 16 was reacted with trimethylsilyl chloride (TMSCl) and

lithium hexamethyldisilazide (LHMDS) to give a silyl enolate, which was electrophilically

ﬂ uorinated with N - ﬂ uorobenzenesulfonamide (NFSI) [46, 47] to yield a mixture of mono-

ﬂ uoro compounds (59% yield), ( ± ) - 17a - 1 and ( ± ) - 17b , as well as the diﬂ uoro compound

( ± ) - 17c (25% yield)after column chromatography on silica gel. The mixture of ( ± ) - 17a - 1

and ( ± ) - 17b was subjected to the Bucherer – Bergs conditions (ammonium carbamate and

potassium cyanide) to yield β - ﬂ uorohydantoin ( ± ) - 18a - 1 (8% yield) and α - ﬂ uorohydan-

toin ( ± ) - 18b (6% yield), respectively, after column chromatography on silica gel and

recrystallization. In a similar manner, diﬂ uorohydantoin ( ± ) - 18c was prepared from com-

pound ( ± ) - 17c under the Bucherer – Bergs conditions (47% yield). Hydantoins ( ± ) - 18a - 1 ,

( ± ) - 18b , and ( ± ) - 18c were hydrolyzed under acidic or basic conditions to yield the corre-

sponding amino acids, ( ± ) - 6a (25% yield), ( ± ) - 6b (21% yield), and ( ± ) - 6c (56% yield),

respectively (see Scheme 3.1 ).

Optically pure (+) - 6a (MGS0008) (64% yield) and its enantiomer ( − ) - 6b (73% yield)

were produced by acidic hydrolysis of carboxylic acids (+) - 19 and ( − ) - 19 , respectively.

Compounds (+) - 19 and ( − ) - 19 were obtained through selective saponiﬁ cation of the ester

moiety of ( ± ) - 18 under basic conditions (93% yield), followed by optical resolution of the

resulting ( ± ) - 19 with ( R ) - and ( S ) - 1 - phenylethylamine [(+) - 19 : 39% yield, ( − ) - 19 : 36%

yield], respectively (see Scheme 3.1 ).

Next, the process chemistry for a large - scale synthesis of (+) - 6a (MGS0008) is pre-

sented (see Scheme 3.2 ) [41] . The reaction of racemic ( ± ) - 16 with TMSCl and LHMDS,

followed by dehydrosilylation with palladium acetate afforded enone ( ± ) - 20 (90% yield),

which was stereoselectively epoxidized using tert - butyl hydroperoxide (TBHP) in the

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

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