NS2359GSK372475 SEP225289 Amri Cns1 2 and Acenta Series

NeuroSearch has developed potent, tropane-based uptake inhibitors [42-44]. Some of the analogs are shown in Fig. 5 and their inhibition data are shown in Table 8. NS-2359 (GSK-372475) is another triple-uptake inhibitor that went into clinical development. This compound was discovered at NeuroSearch and was subsequently licensed to GlaxoSmithKline (GSK) as part of a 5-year R&D alliance in CNS diseases. Although the structure of NS-2359 (GSK-372475) is not yet published, it is believed that NS-2359 is a tropane analog (Fig. 5). Phase I trial results of NS-2359 are reported in NeuroSearch's press release. In an imaging study involving six healthy volunteers receiving daily doses of NS-2359 (0.25-1.0 mg), SPECT showed very clear and specific binding in relevant areas of the brain and clear dose-dependency [45]. In a singledose phase I trial in the UK, this compound is well tolerated [46]. In a clinical trial in 54 volunteers, NS-2359 increased attention and improved the ability to recall verbal information. Following these results, NeuroSearch proposed to focus on the development of NS-2359 for treating ADHD [47]. In 2006, Neu-roSearch announced that GlaxoSmithKline (GSK) initiated a phase II clinical trial of its drug candidate NS2359 (GSK372475) in patients diagnosed with major depressive disorder. These studies will be conducted in multiple centers worldwide and involve several hundred patients.

NeuroSearch Series

<vOMe

<vOMe

N H OMe

N H OMe

H 32

H 32

HN H M^OMe

HN H M^OMe

h ci

N H OEt

N H OEt

H 31

H 31

Cl jO

SEP-225289 AMRI Series

Fig. 5 Structures of compounds in Tables 8 and 9

Table 8 Uptake inhibition data reported in NeuroSearch patents [45-47]

Compd.

32 10 2 10

SEP-225289 is another triple-uptake inhibitor that is under development by Sepracor for the treatment of refractory depression and for generalized anxiety disorder [48,49]. In preclinical studies, SEP-225289 was believed to be a potent and balanced 5-HT, NE, and DA uptake inhibitor, but there is no published uptake inhibition data. SEP-225289 has been put in a randomized, single-blind, placebo-controlled phase I safety, tolerability and pharmacokinetic trial for the treatment of depression [50,51]. The structure is believed to be as shown in Fig. 5, and is closely related to the active, desmethyl metabolite of sibutramine.

Albany Molecular Research Institute is developing biogenic amine transporter inhibitors for the treatment of a range of CNS disorders. Compounds with various combinations of amine transporter inhibition profiles acting selectively or in combination to increase brain levels of 5-HT, NE, or DA were investigated. Bristol-Myers Squibb has an exclusive worldwide license to develop and commercialize the compounds [52]. Preclinical data for compounds AMR-CNS-1 and 2 were disclosed in a recent presentation [53]. Both AMR-CNS-1 and 2 are believed to be novel 4-phenyl tetrahydroisoquinolines with nomifensine as its prototype compound (Fig. 5 and Table 9).

Acenta Discovery Inc. has synthesized a library of piperidine-based no-caine/modafinil hybrids, and some of which display an improved potency at all three monoamine transporters [54,55]. Some interesting compounds, which are highly active at blocking multiple transporters, are listed in Fig. 6 and Table 10. Compound 39 is the most potent and balanced triple-uptake inhibitor reported to date. Some of these compounds were reported as more active in tail suspension tests than desipramine. It was reported at a re-

Table9 In vitro binding and uptake inhibition of AMRI compounds [53]

Compound Uptake inhibition,

Binding inhibition,

(Ki, nM) rat transporters

SERT NET DAT

Compound Uptake inhibition,

Binding inhibition,

(Ki, nM) rat transporters

SERT NET DAT

AMR-CNS-1

14

12.7

22.4

1.3

8.2

21.6

AMR-CNS-2

24

12.6

24.6

3.5

10.4

31.7

Duloxetine

2.8

3.21

202

0.6

3.9

888

35

R=OMe

36

R=NH2

37

R=NHMe

38

R=NMe2

39

R=NHi-Pr

40

R=1 -piperidinyl

Fig. 6 Structures of compounds in Table 10

Table 10 Uptake inhibition data reported in [54,55]

Compd.

[3H]5-HT

[3H]NE

[3H]DA

uptake

uptake

uptake

Ki (nM)

Ki (nM)

Ki (nM)

35

208 ± 47

25 ± 6

80 ± 23

36

557± 150

39 ± 5

159 ± 19

37

110 ± 45

25 ± 2

13 ± 3

38

88 ± 22

27 ± 7

116 ± 46

39

1.1 ± 0.4

0.8 ± 0.1

1.0 ± 0.2

40

4.5 ± 0.8

0.68 ± 0.25

83 ± 1

cent ACS meeting that more systematic in vivo assessments of the selected compounds from this library were on-going to identify potential drug candidates for advancement to pre-development characterization in preparation for a potential IND submission.

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