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A series of isoquinuclidine benzamides as glycine uptake inhibitors for the treatment of schizophrenia are described. Potency, lipophilicity, and intrinsic human microsomal clearance were parameters for optimization. Potency correlated with the nature of the ortho substituents of the benzamide ring, and reductions in lipophilicity could be achieved through heteroatom incorporation in the benzamide and pendant phenyl moieties. Improvements in human CLint were achieved through changes in ring size and the N-alkyl group of the isoquinuclidine itself, with des-alkyl derivatives (40–41, 44) demonstrating the most robust microsomal stability. Dimethylbenzamide 9 was tested in a mouse MK801 LMA assay and had a statistically significant attenuation of locomotor activity at 3 and 10 μmol/kg compared to control.

Previously we reported on the synthesis and properties of a series of highly potent piperidinyl 2-subsituted-3-cyano-1-naphthamide NK1 antagonists that includes 3 and 4. Here we report our efforts to alleviate a troublesome atropisomeric property of those derivatives by introduction of a tethering bridge that, in addition, could be used to lock the resulting cyclic derivatives in a purported NK1 pharmacophore conformation. Using 3 as a starting point, the naphtho[2,1-b][1,5]oxazocine, 17, was found to contain the optimal ring tether size (8) for retaining NK1 activity, was more NK1 versus NK2 selective, and reduced the number of atropisomers from four to two. Cyclic derivatives 29 and 32, which exist as essentially single atropisomers in the purported pharmacophore conformation, were prepared in the closely related naphtho[1,2-f][1,4]oxazocine series as part of an effort to use mono methyl substitution of the tethering bridge as a conformation stabilizing factor. Both 29 and 32 were found to be less active as NK1 antagonists than the non-methylated parent 28 possibly due to methyl group destabilization of receptor interaction. We discuss the above findings in the context of a previously proposed NK1 pharmacophore model and present a further refinement of that model.

We have previously described a series of antagonists that showed high potency and selectivity for the NK1 receptor. However, these compounds also had the undesirable property of existing as a mixture of four interconverting rotational isomers. Through biological and structural analysis of the atropisomers, a binding model was developed and used to guide the design of compounds, which were rigidified by installation of a cyclizing linkage. These compounds existed as a mixture of two atropisomers. Further elaboration of the ring system reinforced the desired conformation and eliminated atropisomeric properties. We found that the region distal to the 8-membered ring system could be modified while retaining NK1 potency, and optimization led to further improvements in the in vivo activity.

Exploration of the SAR around selective NK 2 antagonists, SR48968 and ZD7944, led to the discovery that naphth-1-amide analogues provide potent dual NK 1 and NK 2 antagonists. ZD6021 inhibited binding of [ 3 H]-NKA or [ 3 H]-SP to human NK 1 and NK 2 receptors, with high-affinity ( K i =0.12 and 0.62 nM, respectively). In functional assays ZD6021 had, at 10 −7 M, in human pulmonary artery p K B =8.9 and in human bronchus p K B =7.3, for NK 1 and NK 2 , respectively. Oral administration of ZD6021 to guinea pigs dose-dependently attenuated ASMSP induced extravasation of plasma proteins, ED 50 =0.5 mg/kg, and NK 2 mediated bronchoconstriction, ED 50 =13 mg/kg.

Dipeptide and tripeptide aldehydes have been evaluated as inhibitors of human calpain I. Dipeptide aldehydes are generally equipotent with tripeptide aldehydes. Calpain I possesses a rather stringent requirement for Leu at P2, but accepts a variety of capping groups and amino acids at P1 and P3. Several new peptide aldehydes that are more potent than previously reported calpain I inhibitors have been identified.

Herein, we describe the discovery of inhibitors of norepinephrine (NET) and dopamine (DAT) transporters with reduced activity relative to serotonin transporters (SERT). Two compounds, 8b and 21a, along with nomifensine were tested in a rodent receptor occupancy study and demonstrated dose-dependent displacement of radiolabeled NET and DAT ligands. These compounds were efficacious in a rat forced swim assay (model of depression) and also had activity in rat spontaneous locomotion assay.

An efficient two-step preparation of (6R,7R)-6-hydroxy-7-phenyl-l,4-oxazepan-5-ones (1) starting from aminoethanols and (2R,3S)-3-phenyloxirane-2-carboxylic ethyl ester or potassium salt has been described. The most efficient catalyst identified for the ring closure of the resulting intermediate epoxyamides was Sc(OTf) 3 . By choice of appropriate chiral starting substituted aminoethanol and 3-phenyloxirane-2-carboxylic derivatives, the procedure allows facile synthesis of other single enantiomer 6-hydroxy-7-phenyl-1,4-oxazepan-5-ones.

Through optimization of compounds based on the dual NK(1)/NK(2) antagonist ZD6021, it was found that alteration of two key regions could modulate the balance of NK(1) and NK(2) potency. Substitution of the 2-naphthalene position in analogues of ZD6021 resulted in increased NK(1) potency and thus afforded NK(1) preferential antagonists. Alterations of the piperidine region could then increase NK(2) potency to restore dual NK(1)/NK(2) selectivity. Through these efforts, three novel receptor antagonists from a single chemically related series were identified; two are dual NK(1)/NK(2) antagonists, and the third is an NK(1) preferential antagonist. In this paper, the factors affecting the balance of NK(1) and NK(2) selectivity in this series are discussed and the in vitro and in vivo properties of the novel antagonists are described.

AZD7325 [4-amino-8-(2-fluoro-6-methoxyphenyl)-N-propylcinnoline-3-carboxamide] is a selective GABAAα2,3receptor modulator intended for the treatment of anxiety disorders through oral administration. An interesting metabolic cyclization and aromatization pathway led to the tricyclic core of M9, i.e., 2-ethyl-7-(2-fluoro-6-methoxyphenyl)pyrimido[5,4-c]cinnolin-4(3H)-one. Further oxidative metabolism generated M10 viaO-demethylation and M42 via hydroxylation. An authentic standard of M9 was synthesized to confirm the novel structure of M9 and that of M10 and M42 by liver microsomal incubation of the M9 standard. Metabolites M9, M10, and M42 were either minor or absent in plasma samples after a single dose; however, all became major metabolites in human and preclinical animal plasma after repeated doses and circulated in humans longer than 48 hours after the end of seven repeated doses. The absence of these long circulating metabolites from selected patients’ plasma samples was used to demonstrate patient noncompliance as the cause of unexpected lack of drug exposure in some patients during a Phase IIb outpatient clinical study. The observation of late-occurring and long-circulating metabolites demonstrates the need to collect plasma samples at steady state after repeated doses when conducting metabolite analysis for the safety testing of drug metabolites. All 12 major nonconjugate metabolites of AZD7325 observed in human plasma at steady state were also observed in dog, rat, and mouse plasma samples collected from 3-month safety studies and at higher exposures in the animals than humans. This eliminated concern about human specific or disproportional metabolites.