Daniel Dube

Quinolines as potent 5-lipoxygenase inhibitors: Synthesis and biological profile of L-746,530

Leukotriene biosynthesis inhibitors have potential as new therapeutic agents for asthma and inflammatory diseases. A series of novel substituted 2-cyanoquinolines have been synthesized and the structure activity relationships were evaluated with respect to their ability to inhibit the formation of leukotrienes via the 5-lipoxygenase enzyme. [1S,5R]-2-Cyano-4-(3-furyl)-7-¿3-fluoro-5-[3-(3 alpha-hydroxy-6,8-dioxabicyclo[3.2.1]-octanyl)]phenoxymethyl ¿quinoline (L-746,530) 3 represents a distinct class of inhibitors and possesses in vitro and in vivo potency comparable or superior to naphthalenic analog (L-739,010) 2.

2-Pyridinyl-3-(4-methylsulfonyl)phenylpyridines: Selective and orally active cyclooxygenase-2 inhibitors

A series of novel 2-pyridinyl-3-(4-methylsulfonyl)phenylpyridines has been synthesized and evaluated with respect to their ability to inhibit the isozymes of cyclooxygenase, COX-1, and COX-2. Optimum COX-2 activity is observed by introduction of a substituent at C5 of the central pyridine. 5- Chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine 33 was identified as the optimum compound in this series.

Reductive N-alkylation of amides, carbamates and ureas

Abstract A one pot selective mono N-alkylation of primary amides, thioamides, carbamates and ureas has been developed using aromatic and aliphatic aldehydes as alkylating agents and rifluoroacetic acid triethylsilane as reagents. Application to an efficient synthesis of a primary amine from the corresponding aldehyde via the carbamate intermediate is presented.

NOVEL 1,2-DIARYLCYCLOBUTENES : SELECTIVE AND ORALLY ACTIVE COX-2 INHIBITORS

A series of novel 2,3-diaryl-2-cyclobuten-l-ones have been synthesized and have been evaluated with respect to their ability to inhibit the isozymes of cyclooxygenase, COX-1 and COX-2. 4,4-Dimethyl-2- phenyl-3-(4-(methylsulfonyl)phenyl)cyclobutenone 22 was found to be highly selective for inhibition of COX-2 and was orally active (EDs0 = 2.4 mg/kg) in the rat paw edema model. Copyright

Discovery of MK-0952, a selective PDE4 inhibitor for the treatment of long-term memory loss and mild cognitive impairment

The structure-activity relationship of a novel series of 8-biarylnaphthyridinones acting as type 4 phosphodiesterase (PDE4) inhibitors for the treatment of long-term memory loss and mild cognitive impairment is described herein. The manuscript describes a new paradigm for the development of PDE4 inhibitor targeting CNS indications. This effort led to the discovery of the clinical candidate MK-0952, an intrinsically potent inhibitor (IC(50)=0.6 nM) displaying limited whole blood activity (IC(50)=555 nM). Supporting in vivo results in two preclinical efficacy tests and one test assessing adverse effects are also reported. The comparative profiles of MK-0952 and two other Merck compounds are described to validate the proposed hypothesis.

The discovery and synthesis of highly potent subtype selective phosphodiesterase 4D inhibitors.

The SAR study of a series of 6-aryloxymethyl-8-aryl substituted quinolines is described. Optimization of the series led to the discovery of compound 26b, a highly potent (IC50=0.6 nM) and selective PDE4D inhibitor with a 75-fold selectivity over the A, B, and C subtypes and over 18,000-fold selectivity against other PDE family members. Rat pharmacokinetics and tissue distribution are also summarized.

Addressing time-dependent CYP 3A4 inhibition observed in a novel series of substituted amino propanamide renin inhibitors, a case study

Time-dependent inhibitors of CYPs have the potential to perpetrate drug-drug interactions in the clinical setting. After finding that several leading compounds in a novel series of substituted amino propanamide renin inhibitors inactivated CYP3A4 in an NADPH-dependent and time-dependent manner, a search to identify the cause of this liability was initiated. Extensive SAR revealed that the amide bridge present in compound 1 as a possible culprit. Through the installation of a metabolic soft spot distal to this moiety, potent renin inhibitors with improved CYP profile were identified.

Design and optimization of a substituted amino propanamide series of renin inhibitors for the treatment of hypertension.

The discovery and SAR of a new series of substituted amino propanamide renin inhibitors are herein described. This work has led to the preparation of compounds with in vitro and in vivo profiles suitable for further development. Specifically, challenges pertaining to oral bioavailability, covalent binding and time-dependent CYP 3A4 inhibition were overcome thereby culminating in the identification of compound 50 as an optimized renin inhibitor with good efficacy in the hypertensive double-transgenic rat model.

A novel bicyclic orthoester as a chiral auxiliary: Application to the synthesis of α-hydroxy acids

Abstract Chiral α-keto orthoesters derived from tartaric acid can be reduced diastereoselectively. Hydrolysis affords optically active α-hydroxy acids and the recovered auxiliary.

Renin inhibitors for the treatment of hypertension: Design and optimization of a novel series of pyridone-substituted piperidines

An SAR campaign aimed at decreasing the overall lipophilicity of renin inhibitors such as 1 is described herein. It was found that replacement of the northern appendage in 1 with an N-methyl pyridone and subsequent re-optimization of the benzyl amide handle afforded compounds with in vitro and in vivo profiles suitable for further profiling. An unexpected CV toxicity in dogs observed with compound 20 led to the employment of a time and resource sparing rodent model for in vivo screening of key compounds. This culminated in the identification of compound 31 as an optimized renin inhibitor.