Design and Synthesis of Pyrrolidine-5,5‘-<i>trans-</i>Lactams (5-Oxo-hexahydropyrrolo[3,2-<i>b</i>]pyrroles) as Novel Mechanism-Based Inhibitors of Human Cytomegalovirus Protease. 4. Antiviral Activity and Plasma Stability

Borthwick, Alan D.; Davies, Dave E.; Ertl, Peter; Exall, Anne M.; Haley, Terry; Hart, Graham; Jackson, D.L.; Parry, N. R.; Patikis, Angela; Trivedi, Naimisha; Weingarten, Gordon G.; Woolven, James M.

doi:10.1021/jm030810w

Cited by 68 publications

(28 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In related work, bicyclic lactam derived 'trans-lactam' inhibitors, ultimately derived from more complex natural products, were developed as potent inhibitors of nucleophilic serine proteases [101][102][103][104] (though these have not been d eveloped as PBP/serine β-lactamase inhibitors).…”

Section: Future Science Groupmentioning

confidence: 99%

The Road to Avibactam: The First Clinically Useful Non-β-Lactam Working Somewhat Like a β-Lactam

et al. 2016

View full text Add to dashboard Cite

Avibactam, which is the first non-β-lactam β-lactamase inhibitor to be introduced for clinical use, is a broad-spectrum serine β-lactamase inhibitor with activity against class A, class C, and, some, class D β-lactamases. We provide an overview of efforts, which extend to the period soon after the discovery of the penicillins, to develop clinically useful non-β-lactam compounds as antibacterials, and, subsequently, penicillin-binding protein and β-lactamase inhibitors. Like the β-lactam inhibitors, avibactam works via a mechanism involving covalent modification of a catalytically important nucleophilic serine residue. However, unlike the β-lactam inhibitors, avibactam reacts reversibly with its β-lactamase targets. We discuss chemical factors that may account for the apparently special nature of β-lactams and related compounds as antibacterials and β-lactamase inhibitors, including with respect to resistance. Avenues for future research including non-β-lactam antibacterials acting similarly to β-lactams are discussed.

show abstract

Section: Future Science Groupmentioning

confidence: 99%

The Road to Avibactam: The First Clinically Useful Non-β-Lactam Working Somewhat Like a β-Lactam

et al. 2016

View full text Add to dashboard Cite

show abstract

“…In vitro stability studies are often used during drug discovery because they provide information that can be used to prioritize compounds for in vivo studies and alert researchers to potential liabilities of structural modifications. [7][8][9] This is especially important for drug conjugates such as ADCs and TDCs, which contain linker-drugs that may be susceptible to chemical or enzymatic modifications (e.g., enzyme hydrolysis). 10 Drug conjugates bring the payload to the site of the tumor via the circulatory system.…”

Section: Introductionmentioning

confidence: 99%

Improved translation of stability for conjugated antibodies using an in vitro whole blood assay

Fourie-O’Donohue¹,

Chu²,

Chuh³

et al. 2020

mAbs

View full text Add to dashboard Cite

For antibody-drug conjugates to be efficacious and safe, they must be stable in circulation to carry the payload to the site of the targeted cell. Several components of a drug-conjugated antibody are known to influence stability: 1) the site of drug attachment on the antibody, 2) the linker used to attach the payload to the antibody, and 3) the payload itself. In order to support the design and optimization of a high volume of drug conjugates and avoid unstable conjugates prior to testing in animal models, we wanted to proactively identify these potential liabilities. Therefore, we sought to establish an in vitro screening method that best correlated with in vivo stability. While traditionally plasma has been used to assess in vitro stability, our evaluation using a variety of THIOMAB TM antibody-drug conjugates revealed several disconnects between the stability assessed in vitro and the in vivo outcomes when using plasma. When drug conjugates were incubated in vitro for 24 h in mouse whole blood rather than plasma and then analyzed by affinity capture LC-MS, we found an improved correlation to in vivo stability with whole blood (R 2 = 0.87, coefficient of determination) compared to unfrozen or frozen mouse plasma (R 2 = 0.34, 0.01, respectively). We further showed that this whole blood assay was also able to predict in vivo stability of other preclinical species such as rat and cynomolgus monkey, as well as in human. The screening method utilized short (24 h) incubation times, as well as a custom analysis software, allowing increased throughput and in-depth biotransformation characterization. While some instabilities that were more challenging to identify remain, the method greatly enhanced the process of screening, optimizing, and lead candidate selection, resulting in the substantial reduction of animal studies.

show abstract

“…A similar reactivity range was observed for heterocycles; i.e., an electron-rich indole ring was added in high yield (32k), whereas electron-poor pyridylboronic acids were unreactive (32m, 32n). Copper-mediated direct functionalization of heterocycles with amides and the cross-coupling of bromides using the protocols of Wang and Schreiber (46) and Borthwick et al (47), respectively, were unsuccessful.…”

mentioning

confidence: 99%

Ammonia synthons for the multicomponent assembly of complex γ-lactams

Tan

Martin

Fettinger

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The synthesis of γ-lactams that are unsubstituted at the 1-position (nitrogen) as well as their subsequent N -functionalization is reported. A recently discovered four-component reaction (4CR) is employed with either an ammonia precursor or a protected form of ammonia that can be deprotected in a subsequent synthetic step. These methods represent the first multicomponent assembly of complex lactam structures that are unsubstituted at nitrogen. In addition, two methods for the introduction of nitrogen substituents that are not possible through the original 4CR are reported. X-ray crystallographic analysis of representative structures reveals conformational changes in the core structure that will enable future deployment of this chemistry in the design and synthesis of diverse collections of lactams suitable for the discovery of new biological probes.

show abstract

Design and Synthesis of Pyrrolidine-5,5‘-trans-Lactams (5-Oxo-hexahydropyrrolo[3,2-b]pyrroles) as Novel Mechanism-Based Inhibitors of Human Cytomegalovirus Protease. 4. Antiviral Activity and Plasma Stability

Cited by 68 publications

References 15 publications

The Road to Avibactam: The First Clinically Useful Non-β-Lactam Working Somewhat Like a β-Lactam

The Road to Avibactam: The First Clinically Useful Non-β-Lactam Working Somewhat Like a β-Lactam

Improved translation of stability for conjugated antibodies using an in vitro whole blood assay

Ammonia synthons for the multicomponent assembly of complex γ-lactams

Contact Info

Product

Resources

About