Synthesis and structure-activity relationships of selective norepinephrine reuptake inhibitors (sNRI) with a heterocyclic ring constraint.

The design, synthesis and SAR of a series of heterocyclic ring-constrained norepinephrine reuptake inhibitors are described. As racemates, the best compounds compare favorably with atomoxetine (IC(50)'s<10 nM) in potency at the transporter.

Structure-activity relationships of chiral selective norepinephrine reuptake inhibitors (sNRI) with increased oxidative stability.

The synthesis and SAR of a series of chiral heterocyclic ring-constrained norepinephrine reuptake inhibitors are described. The best compounds compare favorably with atomoxetine in potency (IC(50)s<10 nM), selectivity against the other monoamine transporters, and inhibition of CYP2D6 (IC(50)s>1 microM). In addition, the compounds are generally more stable than atomoxetine to oxidative metabolism and thus are likely to have lower clearance in humans.

Synthesis and structure-activity relationships of retro bis-aminopyrrolidine urea (rAPU) derived small-molecule antagonists of the melanin-concentrating hormone receptor-1 (MCH-R1). Part 1.

The design, synthesis, and SAR of a series of retro bis-aminopyrrolidine ureas are described. Compounds from this series exhibited potent binding affinity and functional activity at MCH-R1, and good oral bioavailability in rat.

Synthesis and structure-activity relationships of retro bis-aminopyrrolidine urea (rAPU) derived small-molecule antagonists of the melanin-concentrating hormone receptor-1 (MCH-R1). Part 2.

The design, synthesis, and SAR of a series of retro bis-aminopyrrolidine ureas are described. Compounds from this series exhibited considerable binding affinity (Ki = 1 nM) and functional activity at MCH-R1, acceptable CYP2D6 inhibition, and good rat brain exposure.

D-amino acid homopiperazine amides: discovery of A-320436, a potent and selective non-imidazole histamine H(3)-receptor antagonist.

Structure-activity relationships of homopiperazine-containing alkoxybiaryl nitriles employing various D-amino acid moieties and their N-furanoyl analogues were undertaken. This led to A-320436, a potent and selective non-imidazole H(3)-receptor antagonist possessing balanced affinity for both rat and human H(3)-receptors. This compound was shown to demonstrate in vitro and in vivo functional antagonism and is non-neurotoxic at doses (i.p.) up to 163 mg/kg in a general observation test.

Synthesis and SAR of aminoalkoxy-biaryl-4-carboxamides: novel and selective histamine H3 receptor antagonists.

Novel 4'-[(NR1R2-1-yl)]-propoxy-biaryl-4-carboxamides were designed and synthesized. All compounds were tested for affinity at histamine H(3)receptors. Most compounds were highly potent and selective for human and rat H(3) receptors and selected examples such as A-349821 showed functional antagonism of H(3) receptors in vitro and in a mouse dipsogenia model.

Synthesis and evaluation of potent pyrrolidine H(3) antagonists.

The synthesis and biological evaluation of novel antagonists of the rat H(3) receptor are described. These compounds differ from prototypical H(3) antagonists in that they do not contain an imidazole moiety, but rather a substituted aminopyrrolidine moiety. A systematic modification of the substituents on the aminopyrrolidine ring was performed using pre-formatted precursor sets, where applicable, to afford several compounds with high affinity and selectivity for the H(3) receptor.

Aminoalkoxybiphenylnitriles as histamine-3 receptor ligands.

Biaryl nitrile amines were prepared and found to have high affinity and selectivity for human and rat histamine H(3) receptors.

Structure-activity relationships of non-imidazole H(3) receptor ligands. Part 1.

SAR studies for novel non-imidazole containing H(3) receptor antagonists with high potency and selectivity for rat H(3) receptors are described. A high throughput screening lead, A-923, was further elaborated in a systematic manner to clarify a pharmacophore for this class of aryloxyalkyl piperazine based compounds.

Structure-activity relationships of non-imidazole H(3) receptor ligands. Part 2: binding preference for D-amino acids motifs.

Structure-activity relationship studies on novel non-imidazole, D-amino acid containing ligands of histamine 3 receptors are presented. A-304121 is a D-alanine piperazine amide with high affinity at the rat H(3) receptor.