Haiqun Tang

Discovery of silyl proline containing HCV NS5A inhibitors with pan-genotype activity: SAR development

HCV NS5A inhibitors have shown impressive in vitro potency profiles in HCV replicon assays thus making them attractive components for inclusion in an all oral fixed dose combination treatment regimen. Herein we describe the research efforts that led to the discovery of silyl proline containing HCV NS5A inhibitors such as 7e and 8a with pan-genotype activity profile and acceptable pharmacokinetic properties.

Design and synthesis of tricyclic sulfones as γ-secretase inhibitors with greatly reduced Notch toxicity

A novel series of tricyclic gamma-secretase inhibitors was designed and synthesized via a conformational analysis of literature compounds. The preliminary results have shown that compounds in this new series have much improved in vitro potency and in vivo profiles. More importantly, they have greatly reduced Notch related toxicity that was associated with previous gamma-secretase inhibitors.

Synthesis and SAR study of tricyclic sulfones as γ-secretase inhibitors: C-6 and C-8 positions.

SAR exploration at C-6 and C-8 positions of the tricyclic sulfone series was carried out. Several functional groups were found to be well tolerated at C-6 and C-8 positions. Selective combination of C-6 and C-8 modification resulted in new tricyclic sulfone analogs with efficacy in in vivo mouse Aβ(40) lowering model.

Discovery of new SCH 39166 analogs as potent and selective dopamine D1 receptor antagonists

A series of novel dopamine D(1) antagonists derived from functionalization of the D-ring of SCH 39166 were prepared. A number of these compounds displayed subnanomolar D(1) activity and more than 1000-fold selectivity over D(2). We found C-3 derivatization afforded compounds with superior overall profile in comparison to the C-2 and C-4 derivatization. A number of highly potent D(1) antagonists were discovered which have excellent selectivity over other dopamine receptors and improved PK profile compared to SCH 39166.

Quality by design (QbD) of amide isosteres: 5,5-Disubstituted isoxazolines as potent CRTh2 antagonists with favorable pharmacokinetic and drug-like properties.

Isoxazoles are frequently used amide isosteres, as shown in the context of discovery of CRTh2 antagonists from amide 1 to isoxazole 2. However, persistent agonism and poor solubility in isoxazole series presented challenges to its further development. Based on the concept of quality by design (QbD), 5,5-disubstituted isoxazolines 3 were introduced. The chirality at 5 position of isoxazolines controlled the switch between two modes of actions, which led to a novel series of pure antagonists. This non-planar motif also conferred a change of shape of these molecules, which avoided flat structures and improved their physical properties.

SAR studies of C2 ethers of 2H-pyrano[2,3-d]pyrimidine-2,4,7(1H,3H)-triones as nicotinic acid receptor (NAR) agonist

Based on in house screening lead compound 1 for the NAR project, SAR studies have been focused on the modification of the C2 ethers of the pyrimidinedione core structure. In this effort, an unpredictable SAR trend was overcome in the alkyl ether and arylalkyl ether series to identify compound 24 with improved in vitro activity compared to nicotinic acid. More consistent and predictable SAR was achieved in the propargyl ether series. Lead compound 41 was identified with good in vitro and in vivo activity in rat, and much improved rat PK profile.

MK-8325: A silyl proline-containing NS5A inhibitor with pan-genotype activity for treatment of HCV

HCV NS5A inhibitors have shown impressive in vitro potency profiles in HCV replicon assays thus making them attractive components for inclusion in an all oral fixed dose combination regimen. Herein, we describe the discovery and characterization of silyl proline-containing HCV NS5A inhibitor MK-8325 with good pan-genotype activity and acceptable pharmacokinetic properties.