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An in vitro screening protocol was used to transform a systemically-distributed SCD inhibitor into a liver-targeted compound. Incorporation of a key nicotinic acid moiety enables molecular recognition by OATP transporters, as demonstrated by uptake studies in transfected cell lines, and likely serves as a critical component of the observed liver-targeted tissue distribution profile. Preclinical anti-diabetic oGTT efficacy is demonstrated with nicotinic acid-based, liver-targeting SCD inhibitor 10, and studies with a close-structural analog devoid of SCD1 activity, suggest this efficacy is a result of on-target activity., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Potent and orally bioavailable SCD inhibitors built on an azetidinyl pyridazine scaffold were identified. In a one-month gDIO mouse model of obesity, we demonstrated that there was no therapeutic index even at low doses; efficacy in preventing weight gain tracked closely with skin and eye adverse events. This was attributed to the local SCD inhibition in these tissues as a consequence of the broad tissue distribution observed in mice for this class of compounds. The search for new structural scaffolds which may display a different tissue distribution was initiated. In preparation for an HTS campaign, a radiolabeled azetidinyl pyridazine displaying low non-specific binding in the scintillation proximity assay was prepared., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

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., (Copyright 2010 Elsevier Ltd. All rights reserved.)

A series of stearoyl-CoA desaturase 1 (SCD1) inhibitors were developed. Investigations of enzyme potency and metabolism led to the identification of the thiadiazole-pyridazine derivative MF-438 as a potent SCD1 inhibitor. MF-438 exhibits good pharmacokinetics and metabolic stability, thereby serving as a valuable tool for further understanding the role of SCD inhibition in biological and pharmacological models of diseases related to metabolic disorders., (Copyright 2009 Elsevier Ltd. All rights reserved.)

Phenanthrene imidazoles 26 and 44 have been identified as novel potent, selective and orally active mPGES-1 inhibitors. These inhibitors are significantly more potent than the previously reported chlorophenanthrene imidazole 1 (MF63) with a human whole blood IC50 of 0.20 and 0.14 microM, respectively. It exhibited a significant analgesic effect in a guinea pig hyperalgesia model at oral doses as low as 14 mg/kg. Both active and selective mPGES-1 inhibitors (26 and 44) have a relatively distinct pharmacokinetic profile and are suitable for clinical development.

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.

Leukotriene biosynthesis inhibitors have potential as therapeutic agents for asthma and inflammatory diseases. A novel series of substituted coumarin derivatives has been synthesized and the structure-activity relationship was evaluated with respect to their ability to inhibit the formation of leukotrienes via the human 5-lipoxygenase enzyme.

The development of a COX-2 inhibitor rofecoxib (MK 966, Vioxx) is described. It is essentially equipotent to indomethacin both in vitro and in vivo but without the ulcerogenic side effect due to COX-1 inhibition.