Robert J. DeVita

Current Status of the Research and Development of Diacylglycerol O-Acyltransferase 1 (DGAT1) Inhibitors

Diacylglycerol O-acyltransferase 1 (DGAT1) has recently become a highly interesting target for metabolic disorders as well as for hepatitis C virus (HCV). DGAT1 processes diacylglycerol to triglycerides in the final step of resynthesis for the absorption of fat across the intestine. Pharmaceutical companies have developed many novel inhibitors of DGAT1, several of which have reached the clinic. Proof of target engagement was achieved with the observation of reduced triglycerides upon treatment of humans with DGAT1 inhibitors; however, there were gastrointestinal adverse events such as nausea, diarrhea, and vomiting. These adverse events have been reported with multiple compounds and are possibly linked to the target because of the recent identification of a human cohort deficient in DGAT1. Clinical studies are continuing in a trial to treat patients with an orphan indication for familial chylomicronemia. The full potential of DGAT1 as a therapeutic target will need to overcome observed clinical adverse events, which are possibly mechanism based. The widespread use of DGAT1 inhibitors will ultimately depend upon a better understanding of how to improve the GI tolerability of these agents.

Novel synthesis of oxadiazoles via palladium catalysis

Abstract Oxadiazoles have been prepared in a one-pot procedure by the palladium-mediated coupling of aryliodides with amidoximes under one atmosphere of carbon monoxide. This reaction proved applicable to both electron-rich and deficient aryliodides.

Identification and initial structure-activity relationships of a novel non-peptide quinolone GnRH receptor antagonist.

Screening of the Merck sample collection for non-peptide compounds with binding affinity for the rat GnRH receptor led to the identification of the substituted quinolone (1) as a lead compound in the search for a non-peptide GnRH receptor antagonist. Substantial improvements in potency (approximately 300 fold) were achieved by addition of an alkyl amine at the 4-position, a 3,5-dimethylphenyl group at the 3-position and 6-nitro-7-chloro-substitution of the 1 H-quinolone core.

Potent antagonists of gonadotropin releasing hormone receptors derived from quinolone-6-carboxamides

SAR studies which focused upon the C-6 position of a recently described series of quinolone gonadotropin releasing hormone antagonists are reported. Synthetic access to diverse quinolone-6-carboxamides was achieved via the palladium-catalyzed amino-carbonylation reactions of iodide 4 with various amines. Amides related to 9y were especially potent, functional antagonists of rat and human GnRH receptors.

Investigation of the 4-O-alkylamine substituent of non-peptide quinolone GnRH receptor antagonists

Synthesis and in vitro activity of the enantiomers of quinolone GnRH antagonist (+/-)-1 are reported. Chiral amino alcohols were prepared from the appropriate cyclic D- or L-amino acids by the Amdt-Eistert homologation followed by reduction of the resulting esters. Incorporation of these pharmacophores was achieved via a novel Mitsunobu alkylation of 4-hydroxyquinolones. The key amine pharmacophore for binding to the rat GnRH receptor was most active in the S-configuration. Ring size was not important for potency with 4, 5, 6, and 7-membered ring amines exhibiting similar potency.

Structure-activity relationships in the amino acid sidechain of L-692,429

Abstract Development of L-692,429, the prototype compound of a novel class of growth hormone (GH) secretagogues1, focused on defining the structure-activity relationships in the amino acid sidechain. Modification of the dimethyl-β-alanine group revealed the basic amine as an essential pharmacophore for GH releasing activity. Evaluation of a variety of amino-substittued derivatives led to the identification of analogs with improved potency.

Quinolones as gonadotropin releasing hormone (GnRH) antagonists: simultaneous optimization of the C(3)-aryl and C(6)-substituents

A series of 3-arylquinolones was prepared and evaluated for their ability to act as gonadotropin releasing hormone (GnRH) antagonists. A variety of substitution patterns of the 3-aryl substituent are described. The 3,4,5-trimethylphenyl substituent (23h) was found to be optimal.

The use of stable-isotopically labeled oleic acid to interrogate lipid assembly in vivo: assessing pharmacological effects in preclinical species

The use of stable isotopically labeled substrates and analysis by mass spectrometry have provided substantial insight into rates of synthesis, disposition, and utilization of lipids in vivo. The information to be gained from such studies is of particular benefit to therapeutic research where the underlying causes of disease may be related to the production and utilization of lipids. When studying biology through the use of isotope tracers, care must be exercised in interpreting the data to ensure that any response observed can truly be interpreted as biological and not as an artifact of the experimental design or a dilutional effect on the isotope. We studied the effects of dosing route and tracer concentration on the mass isotopomer distribution profile as well as the action of selective inhibitors of microsomal triglyceride transfer protein (MTP) in mice and diacylglycerol acyltransferase 1 (DGAT1) in nonhuman primates, using a stable-isotopically labeled approach. Subjects were treated with inhibitor and subsequently given a dose of uniformly 13C-labeled oleic acid. Samples were analyzed using a rapid LC-MS technique, allowing the effects of the intervention on the assembly and disposition of triglycerides, cholesteryl esters, and phospholipids to be determined in a single 3 min run from just 10 μl of plasma.

Mineralocorticoid receptor antagonists

With an increasingly aging population, the need for effective treatment of cardiovascular diseases (eg, heart failure, hypertension, and ischemic heart disease) cannot be overemphasized. The vital importance of mineralocorticoid receptor antagonists for treating cardiovascular conditions has only been appreciated in the last decade. The re-emergence of mineralocorticoid receptor antagonists has provided clinicians with an important tool towards complete blockade of the reninangiotensin-aldosterone axis.

Discovery of MK-4409, a Novel Oxazole FAAH Inhibitor for the Treatment of Inflammatory and Neuropathic Pain

We report herein the identification of MK-4409, a potent and selective fatty acid amide hydrolase (FAAH) inhibitor. Starting from a high throughput screening (HTS) hit, medicinal chemistry efforts focused on optimizing of FAAH inhibition in vitro potency, improving the pharmacokinetic (PK) profile, and increasing in vivo efficacy in rodent inflammatory and neuropathic pain assays.