Milnacipran Analogues

Milnacipran 12, a dual SNRI, is approved for the treatment of depression [42] and is currently in phase 3 trials for the treatment of fibromyalgia [43] (Fig. 15). Interestingly, milnacipran is a polar compound with a log D of ~ 0, and as such is different from many other centrally acting monoamine reuptake inhibitors which are far more lipophilic. The polar nature of mil-nacipran delivers an attractive PK profile in humans, with high bioavail-ability, long half-life and renal elimination of unchanged drug as the primary route of clearance [44]. Despite its polar nature, milnacipran is still believed to exert its pharmacology via central inhibition of serotonin and noradrenaline reuptake. The lack of interaction of milnacipran with P450 enzymes as either substrate or inhibitor reduces the potential for drug-drug interactions, which are highly prevalent for many other marketed monoamine reuptake inhibitors. This attractive physicochemical and PK profile, coupled with clinical efficacy, has prompted several groups to further investigate the SAR in this template, particularly as 12 has relatively weak SNRI activity.

Roggen et al. from the University of Oslo [45] were the first group to investigate enantiomerically pure milnacipran analogues, and their work focused on variations of the aromatic moiety and the impact of stereochemistry on in vitro monoamine reuptake activity (Fig. 16). They found that the (1R, 2S) enantiomer of milnacipran 12a exhibited weak dual SNRI pharmacology, whilst the (1S, 2R) enantiomer 12b was significantly more potent against the logD 0

Fig. 15 Structure and properties of milnacipran 12

logD 0

Fig. 15 Structure and properties of milnacipran 12

ArvA

ArvA

(1S, 2R) isomer 12b Ar= Ph 45b Ar = 2-Thiophene 46b Ar = 3-Thiophene

(1R, 2S) isomer 12a Ar = Ph 45a Ar = 2-Thiophene 46a Ar = 3-Thiophene

(1S, 2R) isomer 12b Ar= Ph 45b Ar = 2-Thiophene 46b Ar = 3-Thiophene

Fig. 16 Structures of milnacipran single enantiomers and analogues 12a/b, 45a/b and 46a/b

Table 4 Uptake inhibition of compounds 12a/b, 45a/b and 46a/b

Compound

[3H]5-HT

[3H]NE

[3H]DA

IC50 (nM)

IC50 (nM)

IC50 (nM)

12a

420

200

10000

12b

120

7

9000

45a

520

1500

970

45b

130

29

1400

46a

250

410

10000

46b

190

19

10000

NET. Variations of the aryl group, for example 45 and 46, generally did not lead to any significant improvements in dual SNRI activity (Table 4).

Chen et al. at Neurocrine Biosciences have investigated the SAR of the mil-nacipran template still further [46-48]. N alkylation of the primary amine was investigated in the racemic series, but in all cases led to a significant drop in potency. The SAR of secondary and tertiary amides was then probed [46] (Fig. 17, Table 5). In general, secondary amides led to a significant drop in activity, with the exception of anilide 47 which had weak NA activity. The authors rationalized this result by a potential favourable n interaction between the inhibitor and transporter protein. Ethyl-phenyl tertiary amide 48 was tenfold more potent and then cyclization to indoline 49 gave a fur-

Fig. 17 Structures of milnacipran analogues 47-49

Fig. 17 Structures of milnacipran analogues 47-49

Table 5 Uptake inhibition of compounds 12 and 47-49

Compound

[3H]5-HT

[3H]NE

[3H]DA

IC50 (nM)

IC50 (nM)

IC50 (nM)

12

420

77

6100

47

> 10000

570

> 10 000

48

4400

63

> 10 000

49

13

4.4

46b Ar = 3-Thiophene

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