Jon Wright

Synthesis and biological evaluations of P4-benzoxaborole-substituted macrocyclic inhibitors of HCV NS3 protease

We disclose here a series of P4-benzoxaborole-substituted macrocyclic HCV protease inhibitors. These inhibitors are potent against HCV NS3 protease, their anti-HCV replicon potencies are largely impacted by substitutions on benzoxaborole ring system and P2∗ groups. P2∗ 2-thiazole-isoquinoline provides best replicon potency. The in vitro SAR studies and in vivo PK evaluations of selected compounds are described herein.

Synthesis and SAR of acyclic HCV NS3 protease inhibitors with novel P4-benzoxaborole moieties

We have synthesized and evaluated a new series of acyclic P4-benzoxaborole-based HCV NS3 protease inhibitors. Structure-activity relationships were investigated, leading to the identification of compounds 5g and 17 with low nanomolar potency in the enzymatic and cell-based replicon assay. The linker-truncated compound 5j was found to exhibit improved absorption and oral bioavailability in rats, suggesting that further reduction of molecular weight and polar surface area could result in improved drug-like properties of this novel series.

Synthesis and Evaluation of Novel Alpha-Amino Cyclic Boronates as Inhibitors of Hcv Ns3 Protease.

We have designed and synthesized a novel series of alpha-amino cyclic boronates and incorporated them successfully in several acyclic templates at the P1 position. These compounds are inhibitors of the HCV NS3 serine protease, and structural studies show that they inhibit the NS3 protease by trapping the Ser-139 hydroxyl group in the active site. Synthetic methodologies and SARs of this series of compounds are described.

Discovery of selective dopamine D4 receptor antagonists: 1-Aryloxy-3-(4-aryloxypiperidinyl)-2-propanols

Abstract High volume screening identified 3-(4-benzylpiperidinyl)-1-naphthoxy-2-propanol as a selective dopamine D4 receptor ligand. A systematic structure-activity study revealed that the benzyl group could be replaced with phenoxy and the naphthalene with phenyl to improve potency almost tenfold. The (R) enantiomer of this compound had a D4 affinity of 2 nM and was over 100-fold weaker at dopamine D2 and D3 receptors.

4-bromo-1-methoxy-N-[2-(4-aryl-1-piperazinyl)ethyl]-2-naphthalenecarboxamides: Selective dopamine D3 receptor partial agonists

Abstract A series of 4-bromo-1-methoxy-N-[2-(4-aryl-1-piperazinyl)ethyl]-2-naphthalenecarboxamide dopamine (DA) D 3 receptor agonists has been identified. These compounds were found to be selective for DA D 3 over D 2 receptors and were shown to be partial to full agonists as measured by stimulation of mitogenesis in D 3 -transfected CHO p-5 cells.

8-amino-6-(arylsulphonyl)-5-nitroquinolines: novel nonpeptide neuropeptide Y1 receptor antagonists

A novel series of 8-amino-6-(arylsulphonyl)-5-nitroquinoline neuropeptide Y1 (NPY) receptor antagonists is reported. The 8-amino and 5-nitro groups were important for NPY1 binding affinity as changes caused large drops in potency. The 6-arylsulphonyl group was necessary; however, substitution on the phenyl was tolerated. The 2-isopropyl analog 21 was a moderately potent, highly selective NPY1 receptor antagonist.

Novel macrocyclic HCV NS3 protease inhibitors derived from α-amino cyclic boronates

A novel series of P2-P4 macrocyclic HCV NS3/4A protease inhibitors with α-amino cyclic boronates as warheads at the P1 site was designed and synthesized. When compared to their linear analogs, these macrocyclic inhibitors exhibited a remarkable improvement in cell-based replicon activities, with compounds 9a and 9e reaching sub-micromolar potency in replicon assay. The SAR around α-amino cyclic boronates clearly established the influence of ring size, chirality and of the substitution pattern. Furthermore, X-ray structure of the co-crystal of inhibitor 9a and NS3 protease revealed that Ser-139 in the enzyme active site traps boron in the warhead region of 9a, thus establishing its mode of action.

Discovery of subtype-selective NMDA receptor ligands: 4-benzyl-1-piperidinylalkynylpyrroles, pyrazoles and imidazoles as NR1A/2B antagonists.

4-Benzyl-1-[4-(1H-imidazol-4-yl)but-3-ynyl]piperidine (8) has been identified as a potent antagonist of the NR1A/2B subtype of the NMDA receptor. When dosed orally, this compound potentiates the effects of L-DOPA in the 6-hydroxydopamine-lesioned rat, a model of Parkinsons disease.

Parallel synthesis of a series of subtype-selective NMDA receptor antagonists.

A series of 1-(heteroarylthioalkyl)-4-benzylpiperidines was rapidly synthesized through the use of parallel synthesis to investigate the binding affinity for the NR1A/2B receptor subtype.

Design and discovery of neuropeptide Y1 receptor antagonists

Neuropeptide Y (NPY) has been the focus of much attention since its discovery as the most abundant peptide in mammalian brain. It has been implicated in many roles in both the periphery and the CNS. The first cloned receptor subtype, Y 1 , has been identified as an important mediator for many of these effects. Potent, selective Y 1 receptor antagonists have been developed and have certainly helped clarify the peripheral roles of NPY and the receptors involved. However, there is still a need for Y 1 antagonists that can be administered peripherally, even orally, and penetrate the CNS. Such compounds would help define the roles of NPY and Y 1 receptors in the CNS, an area rich in potential for novel drug therapy.