Amide Isosteres Research Articles

Identification of potent and selective VEGFR receptor tyrosine kinase inhibitors having new amide isostere headgroups

A novel series of malonamide-type dual VEGFR2/c-Met inhibitors in which one of the amide bonds was replaced by an amide isostere—a trifluoroethylamine unit, was designed, synthesized, and evaluated for their enzymatic and cellular inhibition of VEGFR2 and c-Met enzymes. Optimization of these molecular entities resulted in identification of potent and selective inhibitors of VEGFR2 enzyme.

Isosteric exchange of the acylsulfonamide moiety in Abbott’s Bcl-X L protein interaction antagonist

A multi-component reaction strategy was used for the fast and efficient synthesis of amide isosteres of known Bcl-2 inhibitors capable of disrupting protein–protein interactions. Ugi reaction and a subsequent nucleophilic aromatic substitution reaction provide a versatile path to libraries of compounds similar to Abbott’s acylsulfonamides. Modeling arguments are used to explain the inferior activity of the amide as opposed to the sulfonamide series.

Design, synthesis and antibacterial activity of novel actinonin derivatives containing benzimidazole heterocycles

A series of novel actinonin derivatives containing a benzimidazole heterocycle linked as amide isostere have been designed and synthesized. The structures of all the synthesized compounds were confirmed by analytical and spectroscopic methods. All the compounds were evaluated in vitro against Staphylococcus aureus, Klebsiella pneumoniae, and Sarcina lutea. Among them, compound 1a with unsubstituted benzimidazole ring exhibited potent antibacterial activities.

Preparation and Evaluation of Glycosylated Arginine–Glycine–Aspartate (RGD) Derivatives for Integrin Targeting

Arginine-glycine-aspartate (RGD) derivatives were prepared by a combination of solid-phase and solution-phase synthesis for selective targeting of alpha vbeta 3 integrin expressed in tumors. In order to evaluate the value of a triazole moiety as a proposed amide isostere, the side chain glycosylated cyclic RGD ( cRGD) peptides were synthesized with either a natural amide linkage or a triazole. Affinity of the cRGD constructs for the alpha vbeta 3 integrin was determined in a solid-phase competitive binding assay, showing strong similarity in binding affinity for each of the compounds under evaluation. Furthermore, the in vivo tumor targeting potential of glycosylated cRGD peptides, linked via amide or triazole, was investigated by determining the biodistribution of (125)I-labeled derivatives in mice with tumors expressing alpha vbeta 3. All of the cyclic RGD derivatives showed preferential uptake in the subcutaneous tumors, with the highest tumor-to-blood ratio measured for the triazole-linked glycosylated derivative. The results of the present study are a clear indication of the value of the triazole moiety as a suitable amide isostere in the development of glycosylated peptides as pharmaceuticals.

Aspartic protease inhibitors via C 1-homologation of peptidic aldehydes and studies on reduced amide isosteres

( R)-Configured isophthalic hydroxyethylamines play an important role in the inhibition of β-secretase (BACE1). We present the synthesis of a number of ( S)-configured hydroxyethylamine derivatives via 2-iodoethanol intermediates and the comparison with the ( R)-analogues. An N-substituted indole was investigated as a substitute for the isophthalamide moiety.

A New Approach to N‐3 Functionalized 3,4‐Dihydropyrimidine‐2(1H)‐ones with 1,2,4‐Oxadiazole Group as Amide Isostere via Ionic Liquid‐Phase Technology.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Taking control of P1, P1′ and double bond stereochemistry in the synthesis of Phe-Phe (E)-alkene amide isostere dipeptidomimetics

A protocol for the stereocontrolled independent preparation of both C-2 epimers of Phe-Phe trans-vinyl amide isostere dipeptidomimetics has been devised based on a Wittig-type reaction, in which two chiral building blocks were joined with excellent E-selectivity to give compounds of the type PhePsi[(E)-CH[double bond, length as m-dash]CH]-PheOH.

A new approach to N-3 functionalized 3,4-dihydropyrimidine-2(1 H)-ones with 1,2,4-oxadiazole group as amide isostere via ionic liquid-phase technology

New N-3 functionalized 3,4-dihydropyrimidine-2(1 H)-ones with 1,2,4-oxadiazole group as amide isostere were synthesized in six steps by ionic liquid-phase organic synthesis (IoLiPOS) methodology from ILP bound acetoacetate. The 3,4-dihydropyrimidine-2(1 H)-one (3,4-DHPM) core was prepared in the first step by one-pot three-component Biginelli condensation followed by N-alkylation with chloroacetonitrile. Then the nitrile group appended on the 3,4-DHPM heterocycle was quantitatively transformed into amidoxime. Addition of aliphatic carboxylic anhydride or aromatic carboxylic acid to the amidoxime produced the expected 1,2,4-oxadiazole via the O-acylamidoxime intermediate grafted on the ILP bound 3,4-DHPM using two convergent methods. After cleavage by transesterification under mild conditions, the target compounds were obtained in good overall yields. The structures and the purities of the reaction intermediates in each step were verified easily by routine spectroscopic analysis.

BACE-1 inhibition by a series of ψ[CH 2NH] reduced amide isosteres

A series of β-site amyloid precursor protein cleaving enzyme (BACE-1) inhibitors containing a ψ(CH 2NH) reduced amide bond were synthesized. Incorporation of this reduced amide isostere as a non-cleavable peptide surrogate afforded inhibitors possessing low nanomolar potencies in both an enzymatic and cell-based assay.

Identification of a potent and selective non-basic cathepsin K inhibitor

Based on our previous study with trifluoroethylamine as a P2–P3 amide isostere of cathepsin K inhibitor, further optimization led to identification of compound 22 (L-873724) as a potent and selective non-basic cathepsin K inhibitor. This compound showed excellent pharmacokinetics and efficacy in an ovariectomized (OVX) rhesus monkey model. The volumes of distribution close to unity were consistent with this compound not being lysosomotropic, which is a characteristic of basic cathepsin K inhibitors.

Trifluoroethylamines as Amide Isosteres in Inhibitors of Cathepsin K.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Pseudopeptides and Reduced Amide Isosteres: Structural Probes Potentially Useful as a Subunit Malarial Vaccine Component

AbstractFor Abstract see ChemInform Abstract in Full Text.

Trifluoroethylamines as amide isosteres in inhibitors of cathepsin K

The P2-P3 amide of dipeptide cathepsin K inhibitors can be replaced by the metabolically stable trifluoroethylamine group. The non-basic nature of the nitrogen allows the important hydrogen bond to Gly66 to be made. The resulting compounds are 10- to 20-fold more potent than the corresponding amide derivatives. Compound 8 is a 5 pM inhibitor of human cathepsin K with >10,000-fold selectivity over other cathepsins.

Conformationally Locked Isostere of PhosphoSer−cis-Pro Inhibits Pin1 23-Fold Better than PhosphoSer−trans-Pro Isostere

Stereoisomeric cis and trans substrate analogues for Pin1 were designed and synthesized. The central phosphoSer-Pro core of the Pin1 substrate was replaced by cis and trans amide isosteres in Ac-Phe-Phe-pSer-Psi[(Z and E)CH=C]-Pro-Arg-NH(2), 1 and 2, peptidomimetics. They were synthesized on solid phase in 17% yield for the cis analogue 1, and 16% yield for the trans analogue 2. A second trans amide isostere with a C-terminal N-methylamide 3 was synthesized in 7% yield. The protease-coupled Pin1 assay showed that all three compounds inhibited the Pin1 peptidyl-prolyl isomerase (PPIase) enzymatic activity. The cis isostere 1 was 23 times more potent (K(i) = 1.74 +/- 0.08 muM) than its trans counterpart 2 (K(i) = 40 +/- 2 muM) in competitive inhibition of Pin1. These results suggest that the catalytic site of Pin1 binds cis substrates more tightly in aqueous solution. Antiproliferative activity toward the A2780 human ovarian cancer cell line by the cis and trans analogues correlates with Pin1 inhibition results.

Structure-activity relationships in a series of NPY Y5 antagonists: 3-amido-9-ethylcarbazoles, core-modified analogues and amide isosteres.

Beginning with carbazole 1a, the amide and alkyl substituents were optimized to maintain potency while adding solubilizing groups. Efforts to replace the 3-amino-9-ethylcarbazole core, a known carcinogen, used the SAR generated in the carbazole series for guidance and led to the synthesis of a number of core-modified analogues. In addition, an isosteric series, in which the amide was replaced with an imidazole, was prepared. Two potent new series lacking the putative toxicophore were identified from these endeavors.

Serine-cis-proline and serine-trans-proline isosteres: stereoselective synthesis of (Z)- and (E)-alkene mimics by Still-Wittig and Ireland-Claisen rearrangements.

Two new amide isosteres of Ser-cis-Pro and Ser-trans-Pro dipeptides were designed and stereoselectively synthesized to be incorporated into potential inhibitors of the phosphorylation-dependent peptidylprolyl isomerase Pin1, an essential regulator of the cell cycle. The cis mimic, the (Z)-alkene isomer, was formed through the use of a Still-Wittig [2,3]-sigmatropic rearrangement, while the trans mimic, the (E)-alkene, was synthesized through the use of an Ireland-Claisen [3,3]-sigmatropic rearrangement. Starting from N-Boc-Ser(OBn)-N(OMe)Me, both mimics were synthesized in Boc-protected form suitable for peptide synthesis with an overall yield of 20% in 10 steps for the cis mimic and 13% in eight steps for the trans mimic.

Discovery and evaluation of N-(triazin-1,3,5-yl) phenylalanine derivatives as VLA-4 integrin antagonists

SAR studies aimed at improving the rate of clearance of a series of VLA-4 integrin antagonists by the introduction of a 1,3,5-triazine as an amide isostere are described.

Solvent-dependent stereoselectivity in a Still-Wittig rearrangement: an experimental and ab initio study.

[see reaction]. The Still-Wittig rearrangement gave opposite selectivities for (Z:E)-alkenes in THF (3:1) vs toluene (1:3) in the synthesis of serine-proline dipeptide amide isosteres. Four transition states leading to (Z)-and (E)-alkenes with THF and without (representing toluene) were identified by ab initio calculations at the 3-21G* level. The calculated (Z:E)-ratios with THF (4.7:1) and without THF (1:3.2) suggested that the transition state geometries and energies were well-represented by the calculations.

Conformational studies of irreversible HIV-1 protease inhibitors containing cis-epoxide as an amide isostere.

We have carried out NMR and molecular modeling studies of peptidomimetic HIV-1 protease inhibitors, LB71116: Qc-Asn-Phepsi[(1R,2S)-cis-epoxide]Gly-NH-CH(isopropyl)2 where Qc stands for quinaldic acid and LB71148: Qc-(SMe)Pen(O)2-Phepsi[(1R,2S)-cis-epoxide]Gly-NH-CH(isoprop yl)2 where (SMe)Pen(O)2 stands for S-methyl-S-dioxo-penicillamine. Through conformational calculations and NMR data analysis, we have obtained preferred conformations of the two inhibitors in solution. To our knowledge, this work is one of the first extensive conformational studies of peptidomimetics containing cis-epoxide amide isostere. The resulting preferred conformations contain extended structures. In these conformations, the psi of Phe(cep) is maintained about 130 degrees and the phi angle of (cep)Gly prefers +/- 150 degrees [where Phe(cep) and (cep)Gly are the residues generated by the replacement of the Phe-Gly peptide bond with cis-epoxide]. Two conformations were commonly observed in the preferred conformations of each inhibitor. Through restrained molecular dynamics simulating the hydrogen bond formation between our inhibitor and a water molecule ('flap water'), one of the conformations is assumed as the conformation which can bind to the enzyme without large conformational changes. Recently, we had the opportunity to compare the selected preferred conformation with the binding conformation of LB71116 observed from the X-ray studies of the complex between LB71116 and HIV-1 protease. These two conformations are surprisingly similar to each other. Thus, we can explain high activity and selectivity of our inhibitors to the HIV-1 protease by the similarity between the preferred conformations in solution and the binding conformation.

Potent HIV protease inhibitors containing a novel (2-phenylsulfanyl-1-hydroxyethyl)amide isostere

Based on the concept of bioisosterism, we report the design and synthesis of new protease inhibitors. These new compounds incorporate in their backbone the synthon 2-N-Acyl-2-Phenylsulfanyl-1-Hydroxyethyl (I) which confers on the resulting compounds both in vitro activity on MT 4 infected cells and HIV-1 protease inhibition properties.