Search

The design and optimization of a novel isoxazole S(1) linker for renin inhibitor is described herein. This effort culminated in the identification of compound 18, an orally bioavailable, sub-nanomolar renin inhibitor even in the presence of human plasma. When compound 18 was found to inhibit CYP3A4 in a time dependent manner, two strategies were pursued that successfully delivered equipotent compounds with minimal TDI potential.

An oral bioavailability issue encountered during the course of lead optimization in the renin program is described herein. The low F(po) of pyridone analogs was shown to be caused by a combination of poor passive permeability and gut efflux transport. Substitution of pyridone ring for a more lipophilic moiety (logD>1.7) had minimal effect on rMdr1a transport but led to increased passive permeability (P(app)>10 × 10(-6) cm/s), which contributed to overwhelm gut transporters and increase rat F(po). LogD and in vitro passive permeability determination were found to be key in guiding SAR and improve oral exposure of renin inhibitors.

A new series of indole amide acting as hCRTH2 receptor ligands had been explored and are described herein. Several amide derivatives displaying low nanomolar activity in hCRTH2 binding and whole blood assays were identified. They were found to behave as a full antagonists, exhibiting good selectivity over related prostaglandin receptors. Also, prototypical compounds in this novel series which displayed acceptable CYP profiles and were orally bioavailable in rats were identified.

The incorporation of a carboxylic acid within in a series of 3-amido-4-aryl substituted piperidines (represented by general structure 32) led to the discovery of potent, zwitterionic, renin inhibitors with improved off-target profiles (CYP3A4 time-dependent inhibition and hERG affinity) relative to analogous non-zwitterionic inhibitors of the past (i.e., 3). Strategies to address the oral absorption of these zwitterions are also discussed within.

In this manuscript we wish to report the discovery of MK-7246 (4), a potent and selective CRTH2 (DP2) antagonist. SAR studies leading to MK-7246 along with two synthetic sequences enabling the preparation of this novel class of CRTH2 antagonist are reported. Finally, the pharmacokinetic and metabolic profile of MK-7246 is disclosed.

Highly potent, selective, and bioavailable inhibitors of human, mouse, or rat cathepsin S are described. The key structural features combine a sulfonyl moiety attached to a large group in P2 and a small substituent in P3.

Background/Aims: Total ligation of the left portal vein is thought to induce both hepatocyte apoptosis and necrosis. The pathological impact of partial ligation of a branch of the portal vein has not yet been evaluated. Methods: We studied the degree of hepatocyte injury following 0, 43, 48, 59, 68, 72, 78 and 100% left portal vein stenosis in 200-g Sprague-Dawley male rats. Serum alanine aminotransferase levels, total body weight, and left and right liver lobe weights were measured at 2 and 7 days. Mitosis and 3 H-thymidine labelling indices were measured as markers of proliferation; the apoptotic index and TUNEL stain were used as markers to measure apoptotic cell death. Necrosis was assessed morphologically. All these parameters were evaluated 2 days after ligation. Results: There was a direct relation between the increase in weight of the right lobes and the reduction in weight of the left lobes. The degree of weight change correlated significantly with the degree of stenosis. In the right lobes, mitosis and 3 H-thymidine labelling were increased in proportion to the degree of stenosis. In the left lobes, the decrease in volume of hepatocytes correlated with the degree of ligation, especially in the pericentral areas. Necrosis was identified only when ligation was ≥68%, this being associated with an increase in alanine aminotransferase levels. On the other hand, apoptotic cells were identified in increasing numbers, starting from the lowest degree of ligation to 100% ligation. This was found both morphologically and with TUNEL stain. Conclusions: Partial ligation of the left portal vein induces left liver atrophy through hepatocyte volume loss and apoptosis. Necrosis is found only when the degree of ligation is severe.