Yeeman K. Ramtohul

Development of a Liver-Targeted Stearoyl-CoA Desaturase (SCD) Inhibitor (MK-8245) to Establish a Therapeutic Window for the Treatment of Diabetes and Dyslipidemia

The potential use of SCD inhibitors for the chronic treatment of diabetes and dyslipidemia has been limited by preclinical adverse events associated with inhibition of SCD in skin and eye tissues. To establish a therapeutic window, we embarked on designing liver-targeted SCD inhibitors by utilizing molecular recognition by liver-specific organic anion transporting polypeptides (OATPs). In doing so, we set out to target the SCD inhibitor to the organ believed to be responsible for the therapeutic efficacy (liver) while minimizing its exposure in the tissues associated with mechanism-based SCD depletion of essential lubricating lipids (skin and eye). These efforts led to the discovery of MK-8245 (7), a potent, liver-targeted SCD inhibitor with preclinical antidiabetic and antidyslipidemic efficacy with a significantly improved therapeutic window.

Thiazole analog as stearoyl-CoA desaturase 1 inhibitor

SCD1 inhibition may represent a novel treatment for obesity, type-2 diabetes and related metabolic disorders. A prototype thiazole amide analog 13 (MF-152) was identified as an excellent tool in the study of SCD biology in animals.

SAR and optimization of thiazole analogs as potent stearoyl-CoA desaturase inhibitors.

Elevated stearoyl-CoA desaturase (SCD) activity has been linked to a number of metabolic disorders including obesity and type II diabetes. Compound 3j, a potent SCD inhibitor (human HepG2 IC(50)=1nM) was identified from the optimization of a lead thiazole compound MF-152 with over 100-fold improvement in potency. In a 4-week chronic oral dosing at 0.2mg/kg, 3j gave a robust 24% prevention of body weight gain in mice fed on a high fat diet accompanied with an improved metabolic profile on insulin and glucose levels.

Discovery of potent and liver-targeted stearoyl-CoA desaturase (SCD) inhibitors in a bispyrrolidine series

Inhibition of stearoyl-CoA desaturase (SCD) activity represents a potential novel mechanism for the treatment of metabolic disorders including obesity and type II diabetes. To circumvent skin and eye adverse events observed in rodents with systemically-distributed SCD inhibitors, our research efforts have been focused on the search for new and structurally diverse liver-targeted SCD inhibitors. This work has led to the discovery of novel, potent and structurally diverse liver-targeted bispyrrolidine SCD inhibitors. These compounds possess suitable cellular activity and pharmacokinetic properties to inhibit liver SCD activity in a mouse pharmacodynamic model.

2-Aryl benzimidazoles: Human SCD1-specific stearoyl coenzyme-A desaturase inhibitors

A series of potent, benzimidazole-based SCD inhibitors which demonstrate selectivity for the hSCD1 enzyme over the hSCD5 isoform are described. The compounds possess suitable cellular activity and pharmacokinetic properties which render them capable of inhibiting liver SCD activity in a mouse pharmacodynamic assay. These 2-aryl benzimidazoles may serve as valuable tools for studying selective hSCD1-inhibition.

Bicyclic heteroaryl inhibitors of stearoyl-CoA desaturase: From systemic to liver-targeting inhibitors

Optimization of a lead thiazole amide MF-152 led to the identification of potent bicyclic heteroaryl SCD1 inhibitors with good mouse pharmacokinetic profiles. In a view to target the liver for efficacy and to avoid SCD1 inhibition in the skin and eyes where adverse effects were previously observed in rodents, representative systemically-distributed SCD1 inhibitors were converted into liver-targeting SCD1 inhibitors.

Discovery of potent and liver-selective stearoyl-CoA desaturase (SCD) inhibitors in an acyclic linker series

Elevated levels of stearoyl-CoA desaturase (SCD) activity have been implicated in metabolic disorders such as obesity and type II diabetes. To circumvent skin and eye adverse events observed in rodents with systemically-distributed inhibitors, our research efforts have been focused on the search for new liver-targeting compounds. This work has led to the discovery of novel, potent and liver-selective acyclic linker SCD inhibitors. These compounds possess suitable cellular activity and pharmacokinetic properties to inhibit liver SCD activity in a mouse pharmacodynamic model.

A Multiplexed Cell Assay in HepG2 Cells for the Identification of Delta-5, Delta-6, and Delta-9 Desaturase and Elongase Inhibitors

A multiplexed cell assay has been optimized to measure the activities of fatty acyl-CoA elongase, delta-5 desaturase (Δ5D), delta-6 desaturase (Δ6D), and delta-9 desaturase (Δ9D) together using 14C-labeled tracers in HepG2 cells, which express the human stearoyl-CoA desaturase-1 isoform (SCD1) exclusively. The Δ5 and Δ9 desaturase activities are indexed by the efficient conversion of [1-14C]-eicosatrienoic acid (C20:3, cis-8,11,14) to 14C-arachidonic acid (C20:4, cis-5,8,11,14) and the conversion of [1-14C]-stearic acid to 14C-oleic acid (C18:1, cis-9), respectively. CP-74006 potently blocks the Δ5D activity with an IC50 value of 20 nM and simplifies the metabolism of [1-14C]-α-linolenate (C18:3, cis-9,12,15) by accumulating 14C-eicosatetraenoic acid (C20:4, cis-8,11,14,17) as the major 14C-eicosatrienoic acid (C20:3, cis-11,14,17) and 14C-docosatetraenoic acid (C22:4, cis-10,13,16,19) as the minor metabolites through Δ6 desaturation and elongation. This simplified metabolite spectrum enables the delineation of the Δ6D activity by comparing the combined Δ6D/elongase activity index of the 14C-(C20:4/C18:3) ratio with the corresponding elongation index of the 14C-(C20:3/C18:3) ratio following compound treatment. SC-26196 and sterculic acid specifically inhibit the Δ6D and Δ9D activities with an IC50 value of 0.1 µM and 0.9 µM, respectively. This medium-throughput cell assay provides an efficient tool in the identification of specific desaturase and elongase inhibitors.

Conversion of systemically-distributed triazole-based stearoyl-CoA desaturase (SCD) uHTS hits into liver-targeted SCD inhibitors.

It has been demonstrated that once-a-day dosing of systemically-distributed SCD inhibitors leads to adverse events in eye and skin. Herein, we describe our efforts to convert a novel class of systemically-distributed potent triazole-based uHTS hits into liver-targeted SCD inhibitors as a means to circumvent chronic toxicity.

3,4-Diarylpiperidines as potent renin inhibitors.

The discovery and SAR of a series of potent renin inhibitors possessing a novel 3,4-diarylpiperidine scaffold are described herein. The resulting compound 38 exhibit low nanomolar plasma renin IC(50), had a clean CYP 3A4 profile and displayed micromolar affinity for the hERG channel. Furthermore, it was found to be efficacious in the double transgenic rat hypertension model and show good to moderate oral bioavailability in two animal species.