The structure–activity relationship of a series of tricyclic-sulfonamide compounds 11–32 culminating in the discovery of N-[trans-4-(4,5-dihydro-3,6-dithia-1-aza-benzo[e]azulen-2-ylamino)-cyclohexylmethyl]-methanesulfonamide (15, Lu AA33810) is reported. Compound 15 was identified as a selective and high affinity NPY5 antagonist with good oral bioavailability in mice (42%) and rats (92%). Dose dependent inhibition of feeding was observed after i.c.v. injection of the selective NPY5 agonist ([cPP1–7,NPY19–23,Ala31,Aib32,Gln34]-hPP). In addition, ip administration of Lu AA33810 (10mg/kg) produced antidepressant-like effects in a rat model of chronic mild stress.

Synthesis, SAR and physico-chemical properties of an alkyl aminothiazole series 8 and 16 are described. 2-Pyridylaminothiazole based compounds such as 8c and 16a exhibit high affinity at the NPY5 receptor with desirable cLogPs and solubilities. However, they also suffer from high in vitro and in vivo clearance. Compound 16a partially inhibits the feeding behavior elicited by i.c.v. injection of the selective NPY5 agonist [cPP1–7, NPY19–23, Ala31, Aib32, Gln34]-human pancreatic polypeptide polypeptide (cPP).

Subtype specific ligands are needed to evaluate the therapeutic potential of modulating the brain’s neuropeptide Y system. The benzothiazepine glycinamide 1a was identified as an NPY5 antagonist lead. While having acceptable solubility, the compound was found to suffer from high clearance and poor exposure. Optimization efforts are described targeting improvements in potency, microsomal stability, and PK properties. The low microsomal stability and poor PK properties were addressed through the optimization of the sulfonyl urea and replacement of the benzothiazepinone with other N-heteroaryl glycinamides. For example, the analogous benzoxazine glycinamide 2e has improvements in both affinity (human Y5 Ki 4nM vs 1a 27nM) and microsomal stability (human CLint 2.5L/min vs 1a 35L/min). However the brain penetration (B/P 43/430nM at 10mg/kg PO) remained an unresolved issue. Further optimization by decreasing the hydrogen bond donating properties and PSA provided potent and brain penetrant NPY5 antagonists such as 5f (human Y5 Ki 9nM, B/P 520/840nM 10mg/kg PO).

A novel series of melanin-concentrating hormone (MCH1) receptor antagonists based on combining key fragments from the high-throughput screening (HTS) hits compound 2 (SNAP 7941) and compound 5 (chlorohaloperidol) are described. The resultant analogs, exemplified by compounds 11a-11h, 15a-15h, and 16a-16g, were evaluated in in vitro and in vivo assays for their potential in treatment of mood disorders. From further SAR investigations, N-(3-{1-[4-(3,4-difluorophenoxy)benzyl]-4-piperidinyl}-4-methylphenyl)-2-methylpropanamide (16g, SNAP 94847) was identified to be a high affinity and selective ligand for the MCH1 receptor. Compound 16g also shows good oral bioavailability (59%) and exhibits a brain/plasma ratio of 2.3 in rats. Compound 16g showed in vivo inhibition of a centrally induced MCH-induced drinking effect and exhibited a dose-dependent anxiolytic effect in the rat social interaction model.

Melanin-concentrating hormone (MCH) is involved in the regulation of feeding, water balance, energy metabolism, general arousal and attention state, memory, cognitive functions, and psychiatric disorders. Herein, two new chemical series exemplified by N-[5-(1-{3-[2,2-bis-(4-fluoro-phenyl)-acetylamino]-propyl}-piperidin-4-yl)-2,4-difluoro-phenyl]-isobutyramide (SNAP 102739, 5m) and N-[3-(1-{3-[(S)-2-(4-fluoro-phenyl)-propionylamino]-propyl}-piperidin-4-yl)-4-methylphenyl]-isobutyramide ((S)-6b) are reported. These compounds were designed to improve the pharmacokinetic properties of the high-throughput screening lead compound 1 (SNAP 7941). The MCH1 receptor antagonists 5m and (S)-6b show reasonable pharmacokinetic profiles (rat bioavailability = 48 and 81%, respectively). Compounds 5m and (S)-6b demonstrated the inhibition of a centrally administered MCH-evoked drinking effect, and compound 5m exhibited oral in vivo efficacy in the rat social interaction model of anxiety, with a minimum effective dose = 0.3 mg/kg.

Elevation of glycine levels and activation of the NMDA receptor by inhibition of the glycine transporter 1 (GlyT-1) is a potential strategy for the treatment of schizophrenia. A novel series of GlyT-1 inhibitors have been identified containing,the 2-arylsulfanyl-phenylpiperazine motif. The most prominent member of this series, (R)-4-[5-chloro-2-(4-methoxy-phenylsulfanyl)- phenyl]-2-methyl-piperazin-1-yl-acetic acid (31) is a potent glycine transporter-1 inhibitor (IC50 = 150 nM), which elevated glycine levels in rat ventral hippocampus as measured by microdialysis in vivo at doses of 1.2-4.6 mg/kg s.c. (C) 2004 Elsevier Ltd. All rights reserved.

Central alpha(1)-adrenergic receptors are potential targets for recently developed antipsychotic drugs. Two new 11C labeled potent and selective alpha(1)-adrenoceptor antagonists, 1- [2- [4-[1-(4-fluorophenyl)-5-(2-[(11)C]methyl-tetrazol-5-yl)-1H-indol-3-yl]-1-piperidinyl]ethyl]-imidazolidin-2-one ([(11)C]2) and 1- [2- [4-[1-(4-fluorophenyl)-5-(1-[(11)C]methyl-(1,2,3-triazol-4-yl)-1H-indol-3-yl]-1-piperidinyl]ethyl]-imidazolidin-2-one ([(11)C]3) were prepared and evaluated for imaging of central alpha(1)-adrenergic receptors in the cynomolgus monkey brain. For both compounds, the total brain radioactivity was only about 0.6% of the radioactivity injected i.v. There was no evident binding in regions known to contain alpha(1)-adrenoceptors. This observation suggests that the affinity of the radioligands in primates in vivo is not sufficient to provide a signal for specific binding that can be differentiated from the background. In addition, active efflux by P-glycoprotein may be responsible for the low total brain-uptake of the two radioligands. Both compounds showed a highly polarised and verapamile sensitive transport across monolayers of Caco-2 cells. The total brain-uptake of [(3)H]2 was 6 times higher in mdr1a(-/-) knock-out mice lacking the gene encoding P-glycoprotein compared to wild type mice. Pretreatment of one monkey with Cyclosporin A (15 mg/kg) resulted in 40% higher brain uptake for [(11)C]3 when compared with baseline. These observations support the view that efflux by P-glycoprotein can be of quantitative importance for the total brain-uptake of some PET radioligands.

Novel nonsymmetrical N-bi- and N-terarylpiperazines were synthesized on solid phase via three consecutive palladium-catalyzed cross-coupling reactions in which C-N, C-B, and C-C bonds are formed consecutively.

Three C-11-labelled tracers for the serotonin reuptake site, S-[N-methyl-C-11]citalopram ([C-11]4), S-[N-methyl-d(3)-C-11]citalopram ([C-11]-12), and S-[N-methyl-C-11]citalopram-alpha,alpha-d(2) ([C-11]-13) were synthesized and the distribution of radioactivity after injection of radioligand was examined ex vivo in rats. The deuterated analogue of (S)desmethylcitalopram, (S)-1-(4-fluorophenyl)-1-(3-methylamino-[3-d(2)]-propyl)-1,3-di-hydro-isobenzofuran-5-carbonitrile (11), was synthesized in a multi-step synthesis from escitalopram (4) and used as precursor in the synthesis of [C-11]-13. In analogy with the reported gas phase synthesis of [C-11]methyl iodide the first gas phase synthesis of [C-11]Methyl iodide-d(3) is reported. The H-1/H-2 kinetic isotope effect related to the synthesized compounds were investigated in ex vivo rat studies, where the brain regions of interest to cerebellum ratios of the tracers,[C-11]-4, [C-11]-12 and [C-11]-13 were compared. The ex vivo data indicated no significant differences in binding in any of the investigated brain regions after injection of the three tracers. Copyright (C) 2004 John Wiley Sons, Ltd.

Pretreatment of polystyrene beads with a nonpolar organic solvent is the key for the generation of mechanically robust tablets consisting of neat functionalized polystyrene beads, both alone and in combination with solid reagents or catalysts. The novel dosing methodology provides accurately preweighed tablets in virtually any shape and size and with excellent disintegration properties, speeding up parallel solution and solid phase synthesis. The use of tablets is demonstrated in parallel Mitsunobu and acylation reactions.

Three serotonin reuptake inhibitors where the 5-cyano group in citalopram [1-(3-dimethylamino-propyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (1)] was replaced with a methyl, acetyl and piperidinyl carbonyl group, respectively, were synthesized. In a Stille reaction applying [11C]methyl iodide the labelled compound [5-methyl-11C]{3-[1-(4-fluorophenyl)-5-methyl-1,3-dihydroisobenzofuran-1-yl]-propyl}-dimethylamine ([11C]-2) was synthesized in 60–90% radiochemical yield. [5-carbonyl-11C]{1-[1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-yl]-1-piperidin-1-yl-methanone} ([11C]-3) was synthesized in 62% radiochemical yield in a palladium mediated cross-coupling reaction utilizing [11C]carbon monoxide. The specific activity of [11C]-2 was highly dependent on whether the corresponding trimethyltin or tributyltin precursor was applied. In ex vivo rodent studies compound [11C]-2 exhibited a good blood–brain barrier (BBB) penetration whereas [11C]-3 did not. The brain distribution of [11C]-2 was investigated in a non-human primate using PET. There was a rapid uptake of radioactivity into the brain. Accumulation of the radiotracer was in agreement with the known distribution of serotonin transporters. The maximal thalamus to cerebellum ratio of 1.3 was reached after 85 min and the specific binding was partly blocked after pre-treatment with citalopram. Thus, [11C]-2 does not exhibit appropriate properties as radioligand for visualization of the serotonin transporter in vivo.

Combinatorial chemistry allows the synthesis of libraries of compounds by combination of building blocks or by combinatorial elaboration of a central scaffold.([1,2]) Carbohydrates hold great promise as scaffolds due to their high degree of functionalization, relative conformational rigidity, commercial availability of many stereoisomeric forms, and their well-described chemistry. Hirschmann, Nicolaou, Smith, and their coworkers pioneered the use of carbohydrates as scaffolds in their design and synthesis Of beta-D-glucose derived non-peptide peptidomimetics of the peptide hormone somatostatin (SRIF).([3,4]) However, only relatively few examples on the application of carbohydrates as scaffolds in combinatorial chemistry have been described.([5-11]) For example, Brill et al. anchored a 1,6-anhydro-beta-D-glucopyranoside (levoglucosan) derived epoxide to a solid support and introduced diversity by opening of the support-bound 2,3-epoxide.([9]) Hirschmann et al. employed the opening of a D-glucose derived 1,2-epoxide with a thiol in one of the initial steps towards the synthesis of a library of D-glucose derived compounds. ([10])We reasoned that introduction of all substituents by O-acylation or carbamoylation would give final products with too high a degree of conformational freedom. To introduce substituents directly on the carbohydrate ring and to keep protecting group manipulations on the resin-bound carbohydrate scaffold to a minimum, we decided to prepare a scaffold in which diversity would be introduced by opening of an epoxide. Also, it was a requirement that the scaffold should contain nitrogen, as amines are found in many pharmacologically relevant molecules, e.g., CNS active compounds. We chose inexpensive D-glucosamine as starting material, to prepare a 3,4-epoxide, and to block the C-1 as the methyl glycoside (Scheme 1). Both solution and solid-phase strategies were envisioned; for the solid-phase strategy, the amine could serve as a convenient point for anchoring to a solid support through a Backbone Amide Linker (BAL). ([12,13]) Here we present the synthesis of two new D-glucosamine derived amino epoxides and preliminary studies on opening of one of the epoxides in solution.First, methyl 2-acetamido-2-deoxy-alpha-D-glucopyranoside, 1, easily accessible by Fischer glycosylation, was N-deacetylated by treatment with hydrazine to give known methyl 2-amino-2-deoxy-alpha-D-glucopyranoside 2 (Scheme 1). The N-acetyl group served well here as it was stable to Fischer glycosylation conditions; however, it had to be exchanged with a more labile N-trifluoroacetyl group to allow final deprotection.[GRAPHICS]

Receptor-binding affinities for the alpha(1) adrenoceptor subtypes alpha(1a), alpha(1b) and alpha(1d) for a series of 39 alpha(1) adrenoceptor antagonists derived from the antipsychotic sertindole are reported. The SAR of the compounds with respect to affinity for the alpha(1a), alpha(1b) and alpha(1d) adrenoceptor subtypes as well as affinity obtained by an alpha(1) assay (rat brain membranes) were investigated using a 3D-QSAR approach based on the GRID/GOLPE methodology. Good statistics (r(2)=0.91-0.96; q(2)=0.65-0.73) were obtained with the combination of the water (OH2) and methyl (C3) probes. The combination of steric repulsion and electrostatic attractions explain the affinities of the included molecules. The adrenergic alpha(1a) receptor seems to be more tolerant to large substituents in the area between the indole 5- and 6-positions compared to the adrenergic alpha(1b) and alpha(1d) receptor subtypes. There seems to be minor differences in the position of areas in the alpha(1b) receptor compared to alpha(1a) and alpha(1d) receptors where electrostatic interaction between the molecules and the receptor (OH2 probe) contribute to increased affinity. These observations may be used in the design of new subtype selective compounds. In addition, the model based on biological data from an alpha(1) assay (rat brain membranes) resembles the model for the alpha(1b) adrenoceptor subtype.

A novel linker for the solid-phase synthesis of substituted 1-methylindoles has been developed. The linker is stable under strong basic conditions and compatible with a broad range of chemical transformations as demonstrated by electrophilic and nucleophilic substitution reactions in the 2-position of the indole nucleus. Indoles are cleaved under reductive conditions by use of alane resulting in 1-methylindole derivatives. Sensitive functional groups in the indole moiety such as aldehydes, ketones, esters, imines, and amides are reduced simultaneously.

A new class of 5-heteroaryl-substituted 1-(4-fluorophenyl)-3-(4-piperidinyl)-1H-indoles as highly selective and potentially CNS-active alpha 1-adrenoceptor antagonists is described. The compounds are derived from the antipsychotic sertindole. The structure-affinity relationships of the 5-heteroaryl substituents, and the substituents on the piperidine nitrogen atom were optimized with respect to affinity for alpha 1 adrenoceptors and selectivity in respect to dopamine (D(1-4)) and serotonin (5-HT(1A-1B) and 5-HT(2A,2C)) receptors. The most selective compound obtained, 3-[4-[1-(4-fluorophenyl)-5-(1-methyl-1,2,4-triazol-3-yl)-1H-indol-3-yl]-1-piperidinyl]propionitrile (15c), has affinities of 0.99, 3.2, and 9.0 nM for the alpha(1a), alpha(1b), and alpha(1d) adrenoceptor subtypes, respectively, and a selectivity for adrenergic alpha(1a) receptors in respect to dopamine D2, D3, and D4 and serotonin 5-HT(2A) and 5-HT(2C) higher than 900, comparable to the selectivity of prazosin. In addition, the compound is more than 150-fold selective in respect to serotonin 5-HT(1A) and 5-HT(1B) receptors. A new basic pharmacophore for alpha 1-adrenoceptor antagonists based on a previously reported pharmacophore model for dopamine D2 antagonist is suggested.