Amol Gupte

Synthesis and biological evaluation of isoxazole, oxazole, and oxadiazole containing heteroaryl analogs of biaryl ureas as DGAT1 inhibitors

Diacylglycerol acyltransferase, DGAT1, is a promising target enzyme for obesity due to its involvement in the committed step of triglyceride biosynthesis. Amino biphenyl carboxylic acids, exemplified by compound 4, are known potent inhibitors of hDGAT1. However the high cLogP and poor solubility of these biphenyl analogs might tend to limit their development. We have synthesized and evaluated compounds containing 3-phenylisoxazole, 5-phenyloxazole, and 3-phenyl-1,2,4-oxadiazole biaryl units for their hDGAT1 inhibition. Our aim in synthesizing such heterocyclic analogs was to improve the cLogP and solubility of these molecules while retaining hDGAT1 potency. Several compounds within the 3-phenylisoxazole series exhibited potent hDGAT1 inhibition when evaluated using an in vitro enzymatic assay. Certain promising compounds were studied for their potential to reduce triglyceride levels using an in vivo fat tolerance test in mice and were also evaluated for any possible improvement to their solubility. Compound 40a (IC(50) = 64 nM) with an in vivo plasma triglyceride reduction of 90 percent, and a solubility of 0.43 mg/ml at pH 7.4 may serve as a new lead for developing newer anti-obesity agents.

Synthesis and Biological Evaluation of Phloridzin Analogs as Human Concentrative Nucleoside Transporter 3 hCNT3 Inhibitors

Nucleoside transporter inhibitors have potential therapeutic applications as anticancer, antiviral, cardioprotective and neuroprotective agents. Although quite a few potent inhibitors of the equilibrative nucleoside transporters are known, largely missing are the concentrative nucleoside transporter inhibitors. Phloridzin (3, K(i)=16.00 microM) is a known moderate inhibitor of the concentrative nucleoside transporters. We have synthesized and evaluated analogs of phloridzin at the hCNT3 nucleoside transporter. Within the series of synthesized analogs compound 16 (K(i)=2.88 microM), possessing a ribofuranose sugar unit instead of a glucopyranose as present in phloridzin, exhibited the highest binding affinity at the hCNT3 transporter. Phloridzin and compound 16 have also been shown to be selective for the hCNT3 transporter as compared with the hENT1 transporter. Compound 16 can serve as a new lead which after further modifications could yield selective and potent hCNT3 inhibitors.

Exploration of pyridine containing heteroaryl analogs of biaryl ureas as DGAT1 inhibitors.

The diacylglycerol acyltransferase enzyme, DGAT1, presents itself as a potential target for obesity as this enzyme is dedicated to the final committed step in triglyceride biosynthesis. Biphenyl ureas, exemplified by compound 4, have been reported to be potent hDGAT1 inhibitors. We have synthesized and evaluated 2-pyridyl and 3-pyridyl containing biaryl ureas as hDGAT1 inhibitors. Our aim was to incorporate a heteroaryl scaffold within these molecules thereby improving the cLogP profile and making these compounds more drug-like. Compounds within this series exhibited potent hDGAT1 inhibition when evaluated using an in vitro enzymatic assay. Selected compounds were also subjected to an oral fat tolerance test in mice where the percent triglyceride reduction versus a vehicle control was evaluated. Of the studied heteroaryl analogs compound 44 exhibited an in vitro IC(50) of 17nM and a plasma triglyceride reduction of 79% along with a 12-fold improvement in solubility over the biphenyl urea compound 4.

Evaluation of thiazole containing biaryl analogs as diacylglycerol acyltransferase 1 (DGAT1) inhibitors.

Biphenyl carboxylic acids, exemplified by compound 5, are known potent inhibitors of diacylglycerol acyltransferase, DGAT1, an enzyme involved in the final committed step of triglyceride biosynthesis. We have synthesized and evaluated 2-phenylthiazole, 4-phenylthiazole, and 5-phenylthiazole analogs as DGAT1 inhibitors. The 5-phenylthiazole series exhibited potent DGAT1 inhibition when evaluated using an in vitro enzymatic assay and an in vivo fat tolerance test in mice. Compound 33 (IC50 = 23 nM) exhibiting promising oral pharmacokinetic parameters (AUCinf = 7058 ng h/ml, T1/2 = 0.83 h) coupled with 87 percent reduction of plasma triglycerides in vivo may serve as a lead for developing newer anti-obesity agents.

CoMFA and CoMSIA 3D-QSAR studies on S(6)-(4-nitrobenzyl)mercaptopurine riboside (NBMPR) analogs as inhibitors of human equilibrative nucleoside transporter 1 (hENT1).

3D-QSAR (CoMFA and CoMSIA) studies were performed on human equlibrative nucleoside transporter (hENT1) inhibitors displaying K(i) values ranging from 10,000 to 0.7nM. Both CoMFA and CoMSIA analysis gave reliable models with q2 values >0.50 and r2 values >0.92. The models have been validated for their stability and robustness using group validation and bootstrapping techniques and for their predictive abilities using an external test set of nine compounds. The high predictive r2 values of the test set (0.72 for CoMFA model and 0.74 for CoMSIA model) reveals that the models can prove to be a useful tool for activity prediction of newly designed nucleoside transporter inhibitors. The CoMFA and CoMSIA contour maps identify features important for exhibiting good binding affinities at the transporter, and can thus serve as a useful guide for the design of potential equilibrative nucleoside transporter inhibitors.

Synthesis and evaluation of cyclohexane carboxylic acid head group containing isoxazole and thiazole analogs as DGAT1 inhibitors.

Diacylglycerol acyltransferase 1 (DGAT1) is known to play an important catalytic role in the final step of triglyceride biosynthesis. High fat diet fed DGAT1 knockout mice were resistant to weight gain and exhibited increased insulin and leptin sensitivity thereby indicating a plausible role for DGAT1 inhibitors in the treatment of obesity. 4-Phenylpiperidine-1-carbonyl cyclohexanecarboxylic acid (compound 6, DGAT1 IC50xa0=xa057xa0nM) has been lately reported as a potent DGAT1 inhibitor. In our search for newer scaffolds possessing potent DGAT1 activity we undertook a systematic diversification of compound 6 to identify a 4-(5-phenylthiazole-2-carboxamido)cyclohexanecarboxylic acid scaffold. Further linker optimization of this scaffold identified compound 9e (DGAT1 IC50xa0=xa014.8xa0nM) as a potent DGAT1 inhibitor. Coupled with its inxa0vitro potency, compound 9e also exhibited 112 percent plasma triglyceride reduction at a 3xa0mpk dose in an oral fat tolerance test (FTT) when studied in Swiss mice.