Dipeptide Mimetics Research Articles

Physicochemical determinants of passive membrane permeability: role of solute hydrogen-bonding potential and volume.

The relationship of solute structure with cellular permeability was probed. Two series of dipeptide mimetics consisting of glycine, alanine, valine, leucine, phenylalanine, and cyclohexylalanine with amino acids in the D-configuration were prepared. Partition coefficients for the peptidemimetics were obtained in the octanol/water (log P(octanol/water)), hydrocarbon/octanol (Delta log P), and heptane/ethylene glycol (log P(heptane/glycol)) systems in order to explore the contributions of solute volume, or surface area, and hydrogen-bond potential to the permeability of the solutes. Permeability coefficients were obtained in Caco-2 cell monolayers as a model of the human intestinal mucosa. The results were interpreted in terms of a partition/diffusion model for solute transport where membrane partitioning into the permeability-limiting membrane microdomain is estimated from the solvent partition coefficients. Neither log P(octanol/water) nor Delta log P alone correlated with cellular permeability for all the solutes. In contrast, log P(heptane/glycol) gave a qualitatively better correlation. With regard to solute properties, log P(octanol/water) is predominantly a measure of solute volume, or surface area, and hydrogen-bond acceptor potential, while Delta log P is principally a measure of hydrogen-bond donor strength. Log P(heptane/glycol) contains contributions from all these solute properties. The results demonstrate that both hydrogen-bond potential and volume of the solutes contribute to permeability and suggests that the nature of the permeability-limiting microenvironment within the cell depends on the properties of a specific solute. Collectively, these findings support the conclusion that a general model of permeability will require consideration of a number of different solute structural properties.

New access to α-substituted ( Z)-fluoroalkene dipeptide isosteres utilizing organocopper reagents under ‘reduction–oxidative alkylation (R–OA)’ conditions

( Z)-Fluoroalkene dipeptide isosteres serve as potential dipeptide mimetics. The present paper reports a new access to α-substituted ( Z)-fluoroalkene isosteres utilizing an organocopper-mediated ‘reduction–oxidative alkylation (R–OA)’ reaction.

ChemInform Abstract: Stereoselective Synthesis of Conformationally Constrained Reverse Turn Dipeptide Mimetics

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Small ring constrained peptidomimetics. Synthesis of epoxy peptidomimetics, inhibitors of cysteine proteases.

Different dipeptide analogues containing an oxirane ring in the place of the peptidic bond were prepared starting from naturally occurring amino acids. N-Fmoc-amino aldehydes were transformed into the corresponding methoxyvinyl derivatives through a Wittig reaction, and the addition of PhSeCl gave a series of different alpha-phenylselenyl aldehydes. Mukajiama reaction with silylketene acetals gave an intermediate product that was finally transformed into the desired oxiranyl peptidomimetics. Following this strategy we were able to control three new contiguous stereocenters starting from the enantiomerically pure amino acid. The dipeptide analogues could be used in SPPS on a SASRIN resin as the final epoxides were relatively unstable under acidic conditions. Moreover the synthesis of the single dipeptide mimetics was carried out on solid phase to generate a small library of epoxy peptidomimetics. Some of the products prepared in this work resulted as time-dependent reversible inhibitors of cysteine protease.

Stereoselective synthesis of conformationally constrained reverse turn dipeptide mimetics

Peptide side chains play critical roles in the event of molecular recognition. In order to study the bioactive conformation of parent peptides, a concise and straightforward five-step synthesis of [5.5]-bicyclic reverse turn dipeptide mimetic scaffolds with side chain functionality at the i+1 and i+2 positions has been developed. In the bicyclic structure, two dihedral angles ( ψ 2 and φ 3) are greatly restricted.

N-Formyl hydroxylamine containing dipeptides: generation of a new class of vasopeptidase inhibitors

Four primary zinc-binding pharmacophores (thiols, carboxylates, phosphorus acids, and hydroxamates) have been utilized in generating inhibitors of zinc metalloproteases such as ACE, NEP, the MMPs, and ECE. Although compounds which inhibit the activity of both ACE and NEP (vasopeptidase inhibitors, VPIs) have been reported which incorporate a thiol, carboxylate, or phosphorus acid pharmacophore, the generation of hydroxamate based vasopeptidase inhibitors has remained elusive. Herein we report the first potent vasopeptidase inhibitors which were generated from the incorporation of conformationally restricted dipeptide mimetics to an N-formyl hydroxylamine zinc-binding group. Compounds such as 13c and 13d are among the most potent in this series, exhibiting in vitro activity comparable to other classes of inhibitors.

Synthesis and characterization of bradykinin B(2) receptor agonists containing constrained dipeptide mimics.

We have previously shown that substitution of the D-Tic-Oic dipeptide by a (3S)-[amino]-5-(carbonylmethyl)-2,3-dihydro-1, 5-benzothiazepin-4(5H)-one (D-BT) moiety in the bradykinin B(2) receptor antagonist HOE 140 resulted in a full potent and selective bradykinin B(2) receptor agonist (H-DArg-Arg-Pro-Hyp-Gly-Thi-Ser-D-BT-Arg-OH, JMV1116) exhibiting a high affinity for the human receptor (K(i) 0.7 nM). In the present study, we have investigated the effects of replacement of the D-Tic-Oic moiety by various constrained dipeptide mimetics. The resulting compounds were tested for their binding affinity toward the cloned human B(2) receptor and for their functional interaction with the bradykinin-induced contraction of isolated human umbilical vein. Subsequently, we have designed novel bradykinin B(2) receptor agonists which are likely to be resistant to enzymatic cleavage by endopeptidases and which might represent interesting new pharmacological tools. In an attempt to increase the potency of compound JMV1116, both its N-terminal part and the D-BT moiety were modified. Substitution of the D-arginine residue by a L-lysine residue led to a 10-fold more potent bradykinin B(2) ligand [compound 22 (JMV1465) (K(i) 0.07 nM)], retaining full agonist activity on human umbilical vein. Substitution of the D-BT moiety by a (3S)-[amino]-5-(carbonylmethyl)-2,3-dihydro-8-methyl-1, 5-benzothiazepin-4(5H)-one [D-BT(Me)] moiety led to compound 23 (JMV1609) which exhibited a higher agonist activity (pD(2) = 7.4) than JMV1116 (pD(2) = 6.8).

Structure-based design and synthesis of novel thrombin inhibitors based on phosphinic peptide mimetics

Based on the structure of the thrombin-NAPAP complex, phosphinic dipeptide mimetics were designed as novel thrombin inhibitors. Synthesis and evaluation of these inhibitors revealed a promising lead with an IC 50 of 0.6 μM.

Peptidomimetic compounds that inhibit antigen presentation by autoimmune disease-associated class II major histocompatibility molecules.

We have identified a heptapeptide with high affinity to rheumatoid arthritis-associated class II major histocompatibility (MHC) molecules. Using a model of its interaction with the class II binding site, a variety of mimetic substitutions were introduced into the peptide. Several unnatural amino acids and dipeptide mimetics were found to be appropriate substituents and could be combined into compounds with binding affinities comparable to that of the original peptide. Compounds were designed that were several hundred-fold to more than a thousand-fold more potent than the original peptide in inhibiting T-cell responses to processed protein antigens presented by the target MHC molecules. Peptidomimetic compounds of this type could find therapeutic use as MHC-selective antagonists of antigen presentation in the treatment of autoimmune diseases.

Cyclic Dipeptides. 3.1 Synthesis of Methyl (R)-6-[(tert-Butoxycarbonyl)amino]-4,5,6,7- tetrahydro-2-methyl-5-oxo-1,4-thiazepine-3-carboxylate and Its Hexahydro Analogues: Elaboration of a Novel Dual ACE/NEP Inhibitor

Synthetic routes to highly functionalized 1,4-thiazepinones 2 and 3 have been developed. S-Ac-N-Boc-L-Cys-D(L)-ThrOMe 7a,b have been prepared and, after transformation into the corresponding mesylates, used as the cyclization substrates. Treatment of these compounds with LiAlH(OMe)(3) in THF results in mesylate elimination and thiolacetate reduction, giving rise to both a Michael acceptor (alpha,beta-unsaturated ester) and Michael donor (thiol anion), which undergo in situ intramolecular conjugate addition leading to the stereoselective formation of only two of the four possible stereoisomers of 2. On the other hand, PCC/CaCO(3) oxidation of 7a gave in 80% yield the corresponding ketone 11, which was in turn transformed into the enol triflate 15. Cleavage of the thiolacetate moiety, simultaneous elimination of trifluoromethanesulfonic acid to generate an allene system, and addition of the thiol group to the central carbon of the allene to provide the enantiomerically pure cyclic compound 3 in 85% yield was effected via a one-pot reaction by means of MeONa/MeOH. Thiazepinone 3 is an interesting intermediate for the preparation of conformationally restricted dipeptide mimetics, and its elaboration into the dual ACE/NEP inhibitor 4 is reported.

Expedient Synthesis of α-Substituted α, β- Unsaturated γ-Amino Acids (Dipeptide Mimetics); Wittig Reaction of α-Amino Aldehydes with α- Substituted Alkoxycarbonyl Phosphoranes

Reacting ethoxycarbonyl triphenyl phosphorane with activated alkylhalides in chloroform gave the ylides 4 -12. They react smoothly and in general without racemisation with oc-amino aldehydes resulting in the dipeptide mimetics 15 - 25. Exceptions are the highly labile aldehydes pyridinoalaninal and serinal. Enantiospecificity is proven via enantioselective chromatography.

ChemInform Abstract: Synthesis of Constrained Bicyclic Dipeptide Mimetics.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Synthesis of constrained bicyclic dipeptide mimetics

An efficient synthesis of constrained bicyclic peptidomimetics of (R)-Phe-Pro dipeptide is described. Such mimetics may provide an opportunity to develop inhibitors of thrombin possessing the desired pharmacological features.

Design and synthesis of conformationally constrained arginal thrombin inhibitors

A series of conformationally constrained arginal thrombin inhibitors was prepared starting from 5,6 or 5,7 bicyclic lactamic structures, that an indirect approach of X-ray structure-based drug design indicated as D-Phe-Pro dipeptide mimetics. The tetrahydroquinolyl sulfonamido derivative Ig (LR-D/009) displayed the best inhibitory potency (IC50 = 0.018 μm), with good selectivity over plasmin and trypsin.

Dual Metalloprotease Inhibitors: Mercaptoacetyl-Based Fused Heterocyclic Dipeptide Mimetics as Inhibitors of Angiotensin-Converting Enzyme and Neutral Endopeptidase

A series of 7,6- and 7,5-fused bicyclic thiazepinones and oxazepinones were generated and incorporated as conformationally restricted dipeptide surrogates in mercaptoacyl dipeptides. These compounds are potent inhibitors of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) both in vitro and in vivo. Compound 1a, a 7,6-fused bicyclic thiazepinone, demonstrated excellent blood pressure lowering in a variety of animal models characterized by various levels of plasma renin activity and significantly potentiated urinary sodium, ANP, and cGMP excretion in a cynomolgus monkey assay. On the basis of its potency and duration of action, compound 1a (BMS-186716) was advanced into clinical development for the treatment of hypertension and congestive heart failure.

Conformational analysis of dipeptide mimetics

A compendium of compounds designed as dipeptide mimetics was collected from the literature. Conformational space available to these molecules was evaluated to obtain distance and torsion angle parameters to aid in selection of mimetics for specific target peptides or to explore diversity strategies. Conformations were searched using the RandomSearch algorithm in SYBYL. Data were collected for conformations of each molecule falling within 5 kcal/mol of the minimum. The distance between capping groups on the N- and C-termini of the molecules was measured as well as the pseudotorsion angle about a virtual bond between these two points. Molecules are classified based on the torsion angle space occupied and range of distances spanned by the resulting conformations. A large percentage of the dipeptide mimetics studied here have redundant conformational properties. The distribution of distances for all molecules covers an overall range of 3–15 A, the majority falling between 5–8 A. The angles for the majority of the molecules cover a wide range of torsional space with essentially no gaps in the values they can occupy, although these molecules can be subdivided by the average distance spanned by the allowed conformations. A smaller group of molecules have torsion angles that are restricted to a range of ±60° about the cis position (0°). Representative examples of each group are shown. We conclude that despite the significant effort to devise unique molecular structures as dipeptide mimetics, there is a need for more conformationally restricted compounds to mimic specific peptide conformations, and to complement molecular diversity strategies. © 1997 John Wiley & Sons, Inc. Biopoly 43: 191–217, 1997

Conformational analysis of dipeptide mimetics

A compendium of compounds designed as dipeptide mimetics was collected from the literature. Conformational space available to these molecules was evaluated to obtain distance and torsion angle parameters to aid in selection of mimetics for specific target peptides or to explore diversity strategies. Conformations were searched using the RandomSearch algorithm in SYBYL. Data were collected for conformations of each molecule falling within 5 kcal/mol of the minimum. The distance between capping groups on the N- and C-termini of the molecules was measured as well as the pseudotorsion angle about a virtual bond between these two points. Molecules are classified based on the torsion angle space occupied and range of distances spanned by the resulting conformations. A large percentage of the dipeptide mimetics studied here have redundant conformational properties. The distribution of distances for all molecules covers an overall range of 3–15 Å, the majority falling between 5–8 Å. The angles for the majority of the molecules cover a wide range of torsional space with essentially no gaps in the values they can occupy, although these molecules can be subdivided by the average distance spanned by the allowed conformations. A smaller group of molecules have torsion angles that are restricted to a range of ±60° about the cis position (0°). Representative examples of each group are shown. We conclude that despite the significant effort to devise unique molecular structures as dipeptide mimetics, there is a need for more conformationally restricted compounds to mimic specific peptide conformations, and to complement molecular diversity strategies. © 1997 John Wiley & Sons, Inc. Biopoly 43: 191–217, 1997

Dipeptide mimetics can substitute for the receptor activation domain resulting in highly potent analogues of hPTH(1–36)

A series of hPTH(1–36) analogues were prepared to study the role of the first peptide bond between residues Ser 1-Val 2. Some of these analogues were found to show high affinity binding in intact opossum kidney (OK-1) cells and were very active in their ability to stimulate adenylate cyclase production in intact OK-1 cells, rat UMR 106-06 osteosarcoma cells, and SaOS-2 human osteosarcoma cells. A series of hPTH(1–36) analogues were prepared to study the role of the first peptide bond between residues Ser 1-Val 2. Some of these analogues were found to be very active in vitro.

ChemInform Abstract: β,β‐Dimethylcyclolanthionines (I), New Constrained Dipeptide Mimetics: Synthesis, Crystal Structures, and Conformational Studies.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

β,β‐Dimethylcyclolanthionines, New Constrained Dipeptide Mimetics: Synthesis, Crystal Structures, and Conformational Studies

β,β‐Dimethylcyclolanthionines, New Constrained Dipeptide Mimetics: Synthesis, Crystal Structures, and Conformational Studies