5. NPY Y 5 Receptor Antagonists
5.1. Arylsulfonamide-type and Related NPY Y 5 Receptor Antagonists The first non-peptide Y 5 receptor antagonists with binding affinities in the
micromolar range, e.g. diarylalkanediamines such as JCF 104 (21a) and JCF 105 (21b, Fig. 15), were disclosed in patents by Synaptic Pharma and Eli Lilly & Co.[108,
109]. Moreover, diarylalkanediamines structurally similar to benextramine, which has some affinity to the hY5 receptor (Ki = 5 µM)[25], were prepared, e.g. 21c (Y5: Ki = 1.7 µM)[25], and optimized in subsequent work. Y5 receptor affinity and selectivity could be considerably improved by replacement of one amine center with a (non-basic) arylsulfonamide group and optimization of the connecting chain. A trans -cyclohexane-1,4-diyldimethyl spacer was found to be the most favorable linker between the two nitrogen centers[25]. Examples of the resulting arylsulfonamides are 22a (JCF 109; hY5: Ki = 10 nM, radioligand: [125I]PYY)[103] and 22b (hY5: Ki = 11 nM, radioligand: [125I]PYY)[110].
NH2
Fig. 15: Examples of diarylalkanediamine-, diaminoquinazoline- and arylsulfonamide-type Y5
antagonists.
Based on homology modeling and ligand binding data obtained from studies with a set of receptor mutants, a ligand-receptor interaction model was generated[25]. According to this model a hydrogen bond is possible between the sulfonamide NH and His398 in TM6, which is absent in all other NPY receptor subtypes. Furthermore, the model suggests a salt bridge between the basic amino function of the ligand and Glu211 as well as hydrophobic interactions of the terminal aromatic rings with the receptor protein.
The 2,4-diaminoquinazoline motif was the scaffold of some moderate Y5 ligands with slight Y1/Y5 selectivity[111]. Structural modifications led to compounds with nanomolar affinity for Y5 receptors (e.g. 23, hY5: Ki 10 nM, radioligand:
[125I][Pro34]hPYY)[112].
Table 5: Selected structures and binding data of substituted 2,4-diaminoquinazolines with Y5
affinity[113].
N N HN
N X S R2
R3 R1
24a-h O O
No. R1 R2 X R3 IC50 (nM)a 24ab H H CH2-t-chxc-CH2NH 1-naphthyl 2.9 24b H CH3 CH2-t-chxc-CH2N(CH3) 1-naphthyl 710 24c H H CH2-p-C6H4-CH2NH 1-naphthyl 290 24d phenyl H p-C6H4-CH2 C2H5 0.6 24e phenyl H p-C6H4-CH2 N(CH3)2 0.9 24f phenyl H t-chxc-CH2NH CH3 2
24g H H t-chxc-CH2NH 4-methylphenyl 4
24h H H (CH2)6 1-naphthyl 28
a binding affinities to human NPY Y5 receptors stably expressed in LM(tk−) cells.
b CGP 71683A
c trans-cyclohexane-1,4-diyl
A crucial step towards further increase in Y5 receptor affinity and selectivity was the combination of the diaminoquinazoline moiety with N- cyclohexylmethyl-aryl-sulfonamide substructures like those present in compounds 22. This approach resulted in the synthesis of the Y5 receptor antagonist CGP 71683A (24a, Fig. 15) and analogs at Novartis Pharma[112, 114-116]. Substitution patterns and Y5 receptor binding data of some diaminoquinazolines are exemplarily given in Table 5.
JCF 104 (21a), JCF 109 (22a) and CGP 71683A (24a, Fig. 15 and Table 5) were among the first Y5 antagonistic tools available for the exploration of the occurrence and the pharmacological role of Y5 receptors — especially their influence on feeding
[50, 52, 103, 117-122]. CGP 71683A binds to Y5 receptors with >1000-fold higher affinity than to the Y1, Y2 and Y4 subtypes. It is probably the most intensively studied Y5
antagonist so far. In fact, CGP 71683A (24a) is able to reduce food intake in animals. However, application of the substance in vivo is limited due to unfavorable properties (poor solubility, induction of local inflammatory changes) and significant affinity to other neurotransmitter receptors (e.g. muscarinic acetylcholine receptors) and to the serotonin transporter (5-HT reuptake) which may interfere with the regulation of food consumption[123]. Reports on the peripheral effects of CGP 71683A and other Y5 antagonists were contradictory. Inhibition of PP-induced relaxation of rabbit ileum preparations was originally ascribed to Y5 receptors[124], but further studies suggest that other NPY receptor subtypes (Y4) are involved in this biological response[118].
The combination of the aforementioned structural motifs proved to be very successful. Neither a sulfonamide moiety nor a cyclic hydrocarbon or a quinazoline ring is essential for Y5 receptor affinity. Consequently, the substructures of the Y5 antagonists 22 and 24 were used as scaffolds by many groups to synthesize new potent and selective non-peptide Y5 antagonists. In the following, sulfonamides related to 22 and 24 are subdivided into two chemical classes:
a. analogs of 22, i. e., compounds having a (partially hydrogenated) hydro-carbon system, e.g., tetraline or a homolog,
b. analogs of 24a (CGP 71683), i. e. compounds with other heterocyclic rings in place of the quinazoline.
Similar structures with other groups in place of the sulfonamide are included as analogs in section 5.1, whereas the majority of structurally diverse heterocyclic compounds is summarized in section 5.2.
5.1.1. SULFONAMIDES WITH TETRALINE OR HOMOLOGOUS CYCLIC HYDROCARBON MOIETIES
Recently, Itani et al.[125] described the synthesis of compounds in which, for instance, the tetrahydronaphthalene moiety of 22b was expanded to a benzo[a]cycloheptene one. Additional exchange of the cyclohexane-1,4-diyl group against a piperidine containing central spacer results in 25a (FR 226928, Fig. 16) as the most potent
compound (Y5 IC50 16 nM). Further optimization led to the structures 25b and the non-sulfonamide 25c with subnanomolar affinities[126].
OCH3
Fig. 16: Sulfonamide-type and related Y5 antagonists with piperidine-containing spacer group.
NPY Y5 antagonists with a common 2-aminotetraline motif were disclosed by Ortho-McNeil/R. W. Johnson in patent applications[127-129].
26: IC50 0.9 µM
Fig. 17: Structures of cis-configured 1-substituted 2-aminotetralines and hY5 receptor binding data (IC50 values; displacement of [125I]PYY (80 pM), HEK 293 cells) of some Y5 antagonists with aminotetraline portion[131, 132].
The structure-activity relationships of some α-substituted N-(sulfonamido)alkyl-β -aminotetralines have been the subject of subsequent journal papers[130-132]. Some representative structures (26-29) are depicted in Fig. 17.
The substituted trans-cyclohexane-1,4-diyl scaffold is present in many of the derivatives, though there are equipotent Y5 antagonists with flexible alkyl chains such as n-pentyl instead of cyclohexylmethyl as central spacer. Moreover, analogs of, e.g., 28 with a carboxylic acid amide in place of the sulfonamide group were also found to have high Y5 receptor affinity[107, 129]. Though not exactly matching the features of compounds 22a,b or 24a a large series of sulfonamides and sulfinamides covered in a patent application by Shionogi[133] may be subsumed in this group of Y5 antagonists due to their structural design. Highly potent representative examples are 30a and 30b (Fig. 18) with IC50 values of 0.3 and 0.17 nM for binding affinity (Y5 receptor expressing CHO cells) and 8.4 and 2.6 nM for antagonistic activity in the cAMP assay, respectively[133].
NH O2 S CH3
CHCH3 3 NH
O O
30a N
H O2 S CH3
CHCH3 3 NH
O S
Cl F
30b
Fig. 18: 4-(Sulfonylamino)cyclohexanecarboxylic acid amides.
5.1.2. HETEROCYCLIC ANALOGS OF CGP 71863
Numerous heterocyclic analogs of 24a (CGP 71683A), for instance, compounds with an aminothiazole or aminotriazine group or tricyclic ring systems[134-137] in place of the aminoquinazoline moiety, were disclosed as Y5 antagonists with high affinity and selectivity for the human Y5 receptor. Examples of such compounds (31-35) with Y5 receptor binding data are given in Fig. 19. For some examples, e.g. 31, 32 and 35, hY5 selectivity (vs. hY1, hY2, and hY4 receptors) was demonstrated and the Y5 antagonistic activity was confirmed in a cAMP assay. Tricyclic thiazole 61 and related compounds exhibit an attractive pharmacokinetic profile as selective, orally and centrally available NPY Y5 receptor antagonists. Though 61 inhibited Y5 agonist mediated feeding after oral administration, it did influence free- or fasting-induced feeding in rats[138]. Galiano et al.[139] described benzo[b ]thiophene hydrazide
derivatives with an arylsulfonamidomethylcyclohexyl substructure as selective Y5 receptor antagonists (e.g. 62, IC50 7.7 nM).
Aminotriazoles such as compound 36 were claimed as Y5 antagonists in a patent application by Adir[140]. Substance 36 was reported to displace radiolabeled [125I]PYY from Y5 receptors with an IC50 value of 7 nM (assay not specified) and to lower food
Fig. 19: Heterocyclic analogs of CGP 71683A. Binding constants (hY5) for compounds 31-36 determined in radioligand binding studies on cell membrane preparations[134-136].
5.2. Various Heterocyclic NPY Y5 Receptor Antagonists