The design and synthesis of thrombin inhibitors: analogues of MD805 containing non-polar surrogates for arginine at the P1 position

Baettig, Urs; Brown, Lyndon; Brundish, Derek E.; Dell, C. P.; Furzer, Alex; Garman, Sheila; Janus, Diana; Kane, Peter D.; Smith, Garrick; Walker, Clive V; Cockcroft, Xiaoling; Ambler, J. E.; Mitchelson, Andrew; Talbot, Mark; Tweed, Morris; Wills, Nicholas

doi:10.1016/s0960-894x(00)00282-1

Cited by 12 publications

(4 citation statements)

References 8 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Beyond its potential as a promising starting point for investigating wild‐type PALs promiscuity, the corresponding hydroamination product 2 a represents a valuable pharmacophore. Indeed, the benzoxazole heterocycle is a common structural motif in ligands designed for a wide spectrum of receptors, [32,33] including benzoxazole‐alanine ones [34–36] …”

Section: Figurementioning

confidence: 99%

“…Indeed, the benzoxazole heterocycle is a common structural motif in ligands designed for a wide spectrum of receptors, [32,33] including benzoxazole-alanine ones. [34][35][36] We first selected two PALs from eukaryotic sources, namely, Petroselinum crispum (PcPAL) and Arabidopsis thaliana (AtPAL2) PALs and two PALs from bacterial sources, namely, Anabaena variabilis (AvPAL) and Planctomyces brasiliensis (PbPAL) PALs as candidates since they previously demonstrated broad substrate scope range and high potential in evolvability. After expression and purification as recombinant proteins in Escherichia coli, all wild-type PALs demonstrated catalytic efficiencies in the hydroamination of the natural substrate, cinnamic acid, into L-phenylalanine (Table S5).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Engineered Phenylalanine Ammonia‐Lyases for the Enantioselective Synthesis of Aspartic Acid Derivatives

Buslov,

Desmons,

Duhoo

et al. 2024

Angewandte Chemie

View full text Add to dashboard Cite

Biocatalytic hydroamination of alkenes is an efficient and selective method to synthesize natural and unnatural amino acids. Phenylalanine ammonia‐lyases (PALs) have been previously engineered to access a range of substituted phenylalanines and heteroarylalanines, but their substrate scope remains limited, typically including only arylacrylic acids. Moreover, the enantioselectivity in the hydroamination of electron‐deficient substrates is often poor. Here, we report the structure‐based engineering of PAL from Planctomycesbrasiliensis (PbPAL), enabling preparative‐scale enantioselective hydroaminations of previously inaccessible yet synthetically useful substrates, such as amide‐ and ester‐containing fumaric acid derivatives. Through the elucidation of cryo‐electron microscopy (cryo‐EM) PbPAL structure and screening of the structure‐based mutagenesis library, we identified the key active site residue L205 as pivotal for dramatically enhancing the enantioselectivity of hydroamination reactions involving electron‐deficient substrates. Our engineered PALs demonstrated exclusive a‐regioselectivity, high enantioselectivity, and broad substrate scope. The potential utility of the developed biocatalysts was further demonstrated by a preparative‐scale hydroamination yielding tert‐butyl protected l‐aspartic acid, widely used as intermediate in peptide solid‐phase synthesis.

show abstract

Section: Figurementioning

confidence: 99%

mentioning

confidence: 99%

Engineered Phenylalanine Ammonia‐Lyases for the Enantioselective Synthesis of Aspartic Acid Derivatives

Buslov,

Desmons,

Duhoo

et al. 2024

Angewandte Chemie

View full text Add to dashboard Cite

show abstract

“…The key structural feature of 1 is the thiazolo[5,4- d ]pyrimidine core, a close analogue of purine. This core is found in a variety of pharmacologically relevant molecules with potential indications for diabetes, cancer, and other diseases ( 2 − 5 , Figure ). − Examination of the syntheses of 2 − 5 shows that the assembly of 2-alkyl-thiazolo[5,4- d ]pyrimidines is a nontrivial challenge. The syntheses typically involve thiolation/acylation of 5-aminopyrimidine followed by intramolecular ring closure.…”

Section: Introductionmentioning

confidence: 99%

“…The syntheses typically involve thiolation/acylation of 5-aminopyrimidine followed by intramolecular ring closure. Unfortunately, these steps often require very harsh conditions and the use of highly malodorous reagents and suffer from unsatisfactory yields (5%, 10%, and 24% yield over two steps for 2 , 3 , and 4 , respectively). Here we report the development of an efficient and scalable synthesis of thiazolopyrimidine 1 .…”

Section: Introductionmentioning

confidence: 99%

Scale-Up Synthesis of a TRPV1 Antagonist Featuring a Facile Thiazolo[5,4-d]pyrimidine Formation

Liu

Fitzgerald

Lebsack

et al. 2011

Org. Process Res. Dev.

View full text Add to dashboard Cite

An efficient and practical synthesis of a TRPV1 inhibitor bearing a thiazolo[5,4-d]pyrimidine core was developed. The initial synthesis was modified to facilitate acylation of 5-aminopyrimidine and subsequent thiazole formation. The synthesis features an efficient two-pot, five-step process for the construction of the thiazolo[5,4-d]pyrimidine ring. The new route is concise, chromatography-free, and amenable to large-scale preparation.

show abstract

Peptidomimetics for Drug Design

Estiarte

Rich

2003

Burger's Medicinal Chemistry and Drug Discovery

View full text Add to dashboard Cite

The past and present role of peptidomimetics to drug discovery and protein design is summarized. The historical evolution of this area of research and the current state‐of‐the‐art research strategies are described. A detailed description of each of the peptidomimetics types that have appeared in the literature so far is discussed. Some examples are used to illustrate the drug design process that proceeds from the native peptide to a completely non‐peptide peptidomimetic structure. Special attention is given to important pharmaceutical targets such as the cysteine, metallo, serineor aspartic proteases, integrins, G‐protein–coupled receptors, etc. The principles currently used are highlighted in the discussions of some of the most successful examples. It is obvious that major progress in this area is primarily derived of recent advances in all aspects of science. Molecular modeling, X‐ray crystallography, and high field NMR have greatly contributed to this endeavor. Peptidomimetic inhibitors were traditionally developed by modifying peptide bonds, by mimicking the transition states for enzyme‐catalyzed reactions, or by constraining the conformational mobility of a peptide‐derived chain; the latter was used to overcome some of the pharmacokinetic barriers encountered in using peptides as drugs. Lately, these difficulties have been partially solved with rational drug design of de novo compounds. Several methods have been successfully applied, with noteworthy examples currently in clinical trials, and many others are expected in the near future. It would be wrong, however, to imply that this process is a universal panacea. New ideas are urgently needed to produce clinical candidates faster and to solve some of the undesired pharmacokinetic issues.

show abstract

The design and synthesis of thrombin inhibitors: analogues of MD805 containing non-polar surrogates for arginine at the P1 position

Cited by 12 publications

References 8 publications

Engineered Phenylalanine Ammonia‐Lyases for the Enantioselective Synthesis of Aspartic Acid Derivatives

Engineered Phenylalanine Ammonia‐Lyases for the Enantioselective Synthesis of Aspartic Acid Derivatives

Scale-Up Synthesis of a TRPV1 Antagonist Featuring a Facile Thiazolo[5,4-d]pyrimidine Formation

Peptidomimetics for Drug Design

Contact Info

Product

Resources

About