Novel pyrazinone inhibitors of mast cell tryptase: synthesis and SAR evaluation

Hopkins, Corey R.; Neuenschwander, Kent; Scotese, Anthony C.; Jackson, Sharon; Nieduzak, Thaddeus R.; Pauls, Henry W.; Liang, Guyan; Sides, Keith; Cramer, Dona; Cairns, Jennifer; Maignan, S.; Mathieu, Magali

doi:10.1016/j.bmcl.2004.07.051

Cited by 29 publications

(11 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Pyrazinones have been incorporated into other drug candidate molecules such as inhibitors of human immunodeficiency virus-1 reverse transcriptase (Heeres et al, 2005), caspase-3 (Han et al, 2005), mast cell tryptase (Hopkins et al, 2004), and thrombin (Sanderson et al, 1998). Although metabolism of the majority of the pyrazinone-containing compounds remains unknown, metabolic activation of a series of thrombin inhibitors containing the 6-position substituted pyrazinone was published Singh et al, 2003;Subramanian et al, 2003;Deng et al, 2005;Lin et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Comparative Biotransformation of Pyrazinone-Containing Corticotropin-Releasing Factor Receptor-1 Antagonists: Minimizing the Reactive Metabolite Formation

Zhuo

Hartz²,

Bronson³

et al. 2009

Drug Metab Dispos

View full text Add to dashboard Cite

(S)-5-Chloro-1-(1-cyclopropylethyl)-3-(2,6-dichloro-4-(trifluoromethyl)-phenylamino)pyrazin-2(1H)-one (BMS-665053), a pyrazinone-containing compound, is a potent and selective antagonist of corticotropin-releasing factor receptor-1 (CRF-R1) that showed efficacy in the defensive withdrawal model for anxiety in rats, suggesting its use as a potential treatment for anxiety and depression. In vitro metabolism studies of BMS-665053 in rat and human liver microsomes revealed cytochrome P450-mediated oxidation of the pyrazinone moiety, followed by ring opening, as the primary metabolic pathway. Detection of a series of GSH adducts in trapping experiments suggested the formation of a reactive intermediate, probably as a result of epoxidation of the pyrazinone moiety. In addition, BMS-665053 (20 mg/kg i.v.) underwent extensive metabolism in bile duct-cannulated (BDC) rats. The major drug-related materials in rat plasma were the pyrazinone oxidation products. In rat bile and urine (0-7 h), only a trace amount of the parent drug was recovered, whereas significant levels of the pyrazinone epoxide-derived metabolites and GSH-related conjugates were detected. Further evidence suggested that GSH-related conjugates also formed at the dichloroarylamine moiety possibly via an epoxide or a quinone imine intermediate. Other major metabolites in BDC rat bile and urine included glucuronide conjugates. To reduce potential liability due to metabolic activation of BMS-665053, a number of pyrazinone analogs with different substituents were synthesized and investigated for reactive metabolite formation, leading to the discovery of a CRF-R1 antagonist with diminished in vitro metabolic activation.

show abstract

Section: Discussionmentioning

confidence: 99%

Comparative Biotransformation of Pyrazinone-Containing Corticotropin-Releasing Factor Receptor-1 Antagonists: Minimizing the Reactive Metabolite Formation

Zhuo

Hartz²,

Bronson³

et al. 2009

Drug Metab Dispos

View full text Add to dashboard Cite

show abstract

“…Mechanistic study of the isoquinolines synthesis reported by Alfonsi et al [233] Scheme 56. Mechanistic study of the isoquinolines synthesis reported by Alfonsi et al [233] Derivatives of 2(1H)-pyrazinones are considered as important scaffolds for drug design due to their widespread biological activities [234][235][236][237][238][239]. In this context, Gising et al [237] have reported a rapid and versatile one-pot MW-assisted two steps synthesis of N-1 and C-6 functionalized 3,5-dichloro-2(1H)-pyrazinones 258.…”

Section: Scheme 48 Mw-assisted Ugi 4-component Reaction Leading To Pmentioning

confidence: 99%

“…their widespread biological activities [234][235][236][237][238][239]. In this context, Gising et al [237] have reported a rapid and versatile one-pot MW-assisted two steps synthesis of N-1 and C-6 functionalized 3,5-dichloro-2(1H)-pyrazinones 258.…”

Section: Scheme 48 Mw-assisted Ugi 4-component Reaction Leading To Pmentioning

confidence: 99%

Microwave-Assisted Synthesis of Bioactive Six-Membered Heterocycles and Their Fused Analogues

et al. 2016

View full text Add to dashboard Cite

This review describes the formation of six-membered heterocyclic compounds and their fused analogues under microwave activation using modern organic transformations including cyclocondensation, cycloaddition, multicomponents and other modular reactions. The review is divided according to the main heterocycle types in order of increasing complexity, starting with heterocyclic systems containing one, two and three heteroatoms and their fused analogues. Recent microwave applications are reviewed, with special focus on the chemistry of bioactive compounds. Selected examples from the 2006 to 2015 literature are discussed.

show abstract

“…Recently, a series of inhibitors were prepared via regioselective chloride displacements from a dichloropyrazinone core structure with amines and anilines. Chloride displacements with anilines were accomplished after microwave-assisted heating for 12 min at 120 8C, as illustrated in Scheme 21 [83]. Thus, this nucleophilic substitution did not require any transition-metal catalyst.…”

Section: Serine and Cysteine Protease Inhibitorsmentioning

confidence: 99%

Controlled Microwave Heating as an Enabling Technology: Expedient Synthesis of Protease Inhibitors in Perspective

2007

View full text Add to dashboard Cite

Since the early days of organic chemistry, oil baths, hot plates, metal blocks, and isomantles have been the heating devices of choice for driving chemical reactions. Over the last years, microwave heating has evolved as a well-demonstrated alternative to classic heating with the potential to emerge as the preferred heating method in organic synthesis. In this perspective, we will illustrate that microwave heating has an edge over conventional heating also in medicinal and high-throughput chemistry applications, enabling both an expanded reaction range and the diminishing of reaction times from many hours or days down to minutes. By focusing on the development of protease inhibitors, we present a series of successful lead optimizations starting from complex core structures and using controlled microwave heating as the energy source. In short, hundreds of protease inhibitors have been quickly synthesized under microwave irradiation since the start of our high-speed program back in 1998.

show abstract

Novel pyrazinone inhibitors of mast cell tryptase: synthesis and SAR evaluation

Cited by 29 publications

References 23 publications

Comparative Biotransformation of Pyrazinone-Containing Corticotropin-Releasing Factor Receptor-1 Antagonists: Minimizing the Reactive Metabolite Formation

Comparative Biotransformation of Pyrazinone-Containing Corticotropin-Releasing Factor Receptor-1 Antagonists: Minimizing the Reactive Metabolite Formation

Microwave-Assisted Synthesis of Bioactive Six-Membered Heterocycles and Their Fused Analogues

Controlled Microwave Heating as an Enabling Technology: Expedient Synthesis of Protease Inhibitors in Perspective

Contact Info

Product

Resources

About