Piperidine Containing Structures

With the aim of identifying additional new chemical entities capable of 5-HT2C receptor blockade, GlaxoSmithKline developed a pharmacophore model that was used to synthesize different chemical classes of compounds (Fig. 3.2). The model was validated by means of structure-activity relationships derived from available data of a wide range of antagonists that interacted with the receptor in the same

Fig. 3.2 Pharmacophore model for the 5-HT2C antagonists. Pharmacophoric features: HBA H-bond acceptor, PI positive ionizable, HYD hydrophobic, AR aromatic ring


Fig. 3.2 Pharmacophore model for the 5-HT2C antagonists. Pharmacophoric features: HBA H-bond acceptor, PI positive ionizable, HYD hydrophobic, AR aromatic ring manner. It demonstrated the key role played by both the positive ionizable group and the H-bond acceptor functionality to achieve high 5-HT2C affinity.

A first group of bisaryl imidazolidin-2-ones is exemplified by the structure of compound 33 (Fig. 3.3) which showed high 5-HT2C receptor affinity (p^ = 9.1) and >400-fold selectivity over 5-HT2A and 5-HT2B receptors. However, the compounds belonging to this class presented high in vivo clearance. The structure-activity relationships of these compounds indicated that the dihalosubstitution on the phe-nyl ring was preferred over the monosubstitution; the replacement of the piperidine ring by a morpholine or by a dimethylamino was well tolerated; the shifting of the ethoxyamino chain caused a marked loss in affinity; and the introduction of a double bond in the five-membered ring caused a loss in affinity (Goodacre et al. 2005).

A series of diaryl substituted pyrrolidinones and pyrrolones, which fitted the pharmacophore model described above, has been studied. The most relevant compound was 34 (Fig. 3.3), which showed the best compromise between pharmacological and pharmacokinetic properties (p^s: 5-HT2C=8.5; 5-HT2A=6.1; 5-HT2B < 6.1). The different decoration of the scaffold led to different values in potency. In particular, a methoxy group on the phenyl ring was favored; substitution of the left hand side aromatic portion was well tolerated with respect to the potency and selectivity; the piperidine was the best basic moiety; hydrogenation of the lactamic double bond affected negatively both affinity and metabolic stability (Micheli et al. 2006).

Conformational analysis of the template 34 (Fig. 3.3) showed a rather small dihedral angle between the lactam and the adjacent left hand side phenyl ring for the global minimum conformer. Therefore, it was suggested that, if the conformation most relevant for binding at the target receptor was similar to the minimum energy conformer, tricyclic indole derivatives with a general formula exemplified by 35 (Fig. 3.3) might be able to bind to the 5-HT2C receptor. Moreover, inclusion of the carbon-carbon double bond of the lactam in an aromatic ring could modulate the overall properties of the resulting compounds by profoundly changing the chemical nature of this fragment. The new derivatives retained the same binding profile as the opened counterparts. The change from vinylic to aromatic nature of the carbon-carbon double bond of the lactam ring was compatible with a favorable profile at both receptor and in vivo level. For example, compound 35 showed pK. = 8.5 at 5-HT2C receptors, pK. = 6.9 at 5-HT2A and pK. = 7.4 at 5-HT2B. This compound also possessed good oral bioavailability. The structural modifications summarized in Fig. 3.3 left unchanged the pharmacological profile of the compounds (Hamprecht et al. 2007a).

Rather than using an indole system as in 35, phenyl fusion was considered as a further option to include the double bond of the pyrrolidone ring into a rigid framework. Following this criterion, a series of isoindolones was evaluated and the most notable example of this series was the compound 36 (Fig. 3.3). The affinity to the 5-HT2C receptor was high (pK=8.6) and the selectivities over the 5-HT2A and 5-HT2B subtypes higher than 100-fold. As far as the structure-activity relationships are concerned, evaluation of mono- and disubstitution pattern on the isoindolinone ring indicated that the 6,7-dichloro substitution was preferred. Variation of the basic

Fig. 3.3 The evolution of a set of 5-HT2C receptor antagonists developed by GlaxoSmithKline of the basis of pharmacophore model reported in Fig. 3.2

heterocycle indicated that various substituted piperidines were tolerated, as well as ring enlargement. a-Methylation to the basic nitrogen also led to slightly reduced target affinities in the case of replacement with morpholine. In line with previous findings, 4-methylpiperidine derivatives demonstrated the most favorable pharma-cokinetic properties (Hamprecht et al. 2007b).

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