38675-10-4

Usage

Uses

Used in Pharmaceutical Industry:
BOC-D-PHE-PRO-OH is used as a reactant for the preparation of Phe-Pro-p-amidinobenzylamine analogs, which are potent and highly selective thrombin inhibitors. These inhibitors play a crucial role in the development of antithrombotic drugs, targeting the enzyme thrombin responsible for blood clot formation. By inhibiting thrombin, these analogs can help prevent clot-related disorders and potentially save lives in cases of stroke, heart attack, and other thrombotic events.
Additionally, due to its chemical properties and reactivity, BOC-D-PHE-PRO-OH may also be utilized in other pharmaceutical applications, such as the synthesis of other bioactive peptides or as an intermediate in the production of various drugs. However, further information would be required to confirm these additional uses.

InChI:InChI=1/C19H26N2O5/c1-19(2,3)26-18(25)20-14(12-13-8-5-4-6-9-13)16(22)21-11-7-10-15(21)17(23)24/h4-6,8-9,14-15H,7,10-12H2,1-3H3,(H,20,25)(H,23,24)/t14-,15+/m1/s1

Upstream product

• 64471-88-1 (S)-benzyl 1-((R)-2-(tert-butoxycarbonylamino)-3-phenylpropanoyl)pyrrolidine-2-carboxylate 
• 147-85-3 L-proline 
• 18942-49-9 Boc-D-Phe-OH 
• 16652-71-4 benzyl (2S)-2-pyrrolidinecarboxylate hydrochloride 
• 41324-66-7 H-Pro-OBzl 
• 126251-09-0 Boc-D-Phe-L-Pro-OMe 
• 19901-50-9 methyl (2R)-2-(t-butoxycarbonylamino)-3-phenylpropionate 
• 2577-48-2 methyl (2S)-pyrrolidine carboxylate 

Downstream Products

• 198902-77-1 diphenyl 1-<amino>-2-(4-amidinophenyl)ethanephosphonate 
• 183595-83-7 ((R)-1-Benzyl-2-{(S)-2-[2-(4-cyano-phenyl)-ethylcarbamoyl]-pyrrolidin-1-yl}-2-oxo-ethyl)-carbamic acid tert-butyl ester 
• 172348-68-4 tert-butyl ((R)-1-((2S)-2-((4-cyanobenzyl)carbamoyl)pyrrolidin-1-yl)-1-cyclohexyl-2-oxoethyl)carbamate 
• 172348-61-7 (1-benzyl-2-{2-[4-(tert-butoxycarbonylamino-methyl)-benzylcarbamoyl]-pyrrolidin-1-yl}-2-oxo-ethyl)-carbamic acid tert-butyl ester 
• 162167-93-3 {[4-({[1-(2-tert-butoxycarbonylamino-3-phenyl-propionyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-piperidin-1-yl]-tert-butoxycarbonylimino-methyl}-carbamic acid tert-butyl ester 
• 80079-63-6 (S)-1-((R)-2-Amino-3-phenyl-propionyl)-pyrrolidine-2-carboxylic acid (4-guanidino-butyl)-amide 

Relevant academic research and scientific papers

Engineering DNA-Templated Nonribosomal Peptide Synthesis

Diffusive escape of intermediates limits the rate enhancement that nanocontainers or macromolecular scaffolds can provide for artificial biocatalytic cascades. Nonribosomal peptide synthetases (NRPSs) naturally form gigantic assembly lines and prevent esc

CHROMOGENIC AND FLUOROGENIC PEPTIDE SUBSTRATES FOR THE DETECTION OF SERINE PROTEASE ACTIVITY

The present invention relates to chromogenic and fluorogenic substrates that can be used for the highly sensitive and selective detection of the activity of serine proteases. The present invention further relates to methods for the detection of the activi

A chromogenic and fluorogenic peptide substrate for the highly sensitive detection of proteases in biological matrices

The synthesis and application of a novel type of chromogenic and fluorogenic substrate for protease detection is described. The outstanding performance of the tripeptide substrates is exemplified by specific fluorescence detection of thrombin and factor X

Total synthesis of the marine-derived cyclic depsipeptide alternaramide

The first synthesis of the marine fungus derived natural product alternaramide is described using solution phase coupling protocols and via a macrolactonization and macrolactamization route. The structure of alternaramide was confirmed and was supported b

Pro-Soft Val-boroPro: A strategy for enhancing in vivo performance of boronic acid inhibitors of serine proteases

Val-boroPro, 1, is a potent, but relatively nonspecific inhibitor of the prolyl peptidases. It has antihyperglycemic activity from inhibition of DPPIV but also striking anticancer activity and a toxicity for which the mechanisms are unknown. 1 cyclizes at

Enhancement of hydrophobic interactions and hydrogen bond strength by cooperativity: Synthesis, modeling, and molecular dynamics simulations of a congeneric series of thrombin inhibitors

Accurately predicting the binding affinity of ligands to their receptors by computational methods is one of the major challenges in structure-based drug design. One of the potentially significant errors in these predictions is the common assumption that the ligand binding affinity contributions of noncovalent interactions are additive. Herein we present data obtained from two separate series of thrombin inhibitors containing hydrophobic side chains of increasing size that bind in the S3 pocket and with, or without, an adjacent amine that engages in a hydrogen bond with Gly 216. The first series of inhibitors has a m-chlorobenzyl moiety binding in the S1 pocket, and the second has a benzamidine moiety. When the adjacent hydrogen bond is present, the enhanced binding affinity per ?2 of hydrophobic contact surface in the S3 pocket improves by 75% and 59%, respectively, over the inhibitors lacking this hydrogen bond. This improvement of the binding affinity per ?2 demonstrates cooperativity between the hydrophobic interaction and the hydrogen bond.

In-depth study of tripeptide-based α-ketoheterocycles as inhibitors of thrombin. Effective utilization of the S1′ subsite and its implications to structure-based drug design

Thrombin inhibitors are potentially useful in medicine for their anticoagulant and antithrombotic effects. We synthesized and evaluated diverse heterocycle-activated ketones based on the D-Phe-Pro-Arg, and related thrombin active-site recognition motifs, as candidate inhibitors. The peptide-based α-ketoheterocycles were typically prepared by either an imidate or a Weinreb amide route (Schemes 1 and 2), the latter of which proved to be more general. Test compounds were generally assayed for inhibition of human α-thrombin and bovine trypsin. From a structure-based design standpoint, the heterocycle allows one to explore and adjust interactions within the S1′ subsite of thrombin. The preferred α-ketoheterocycle is a π-rich 2-substituted azole with at least two heteroatoms proximal to the carbon bearing the keto group, and a preferred thrombin inhibitor is 2-ketobenzothiazole 3, with a potent Ki value of 0.2 nM and ca. 15-fold selectivity over trypsin. 2-Ketobenzothiazole 13 exhibited exceedingly potent thrombin inhibition (Ki = 0.000 65 nM; slow tight binding). Several α-ketoheterocycles had thrombin Ki values in the range 0.1-400 nM. The "Arg" unit in the α-ketoheterocycles can be sensitive to stereomutation under mildy basic conditions. For example, 2-ketothiazoles 4 and 59 readily epimerize at pH 7.4, although they are fairly stable stereochemically at pH 3-4; thus, suitable conditions had to be selected for the enzymatic assays. Lead D-Phe-Pro-Arg 2-benzothiazoles 3, 4, and 68 displayed good selectivity for thrombin over other key coagulation enzymes (e.g., factor Xa, plasmin, protein Ca, uPA, tPA, and streptokinase); however, their selectivity for thrombin over trypsin was modest (50 = 30-40 nM). They also proved to be potent anticoagulant/ antithrombotic agents in vivo on intravenous administration, as determined in the canine arteriovenous shunt (ED50 = 0.45-0.65 mg/kg) and the rabbit deep vein thrombosis (ED50 = 0.1-0.4 mg/kg) models. Intravenous administration of 3, and several analogues, to guinea pigs caused hypotension and electrocardiogram abnormalities. Such cardiovascular side effects were also observed with some nonguanidine inhibitors and inhibitors having recognition motifs other than D-Phe-Pro-Arg. 2-Benzothiazolecarboxylates 4 and 68 exhibited significantly diminished cardiovascular side effects, and benzothiazolecarboxylic acid 4 had the best profile with respect to therapeutic index. The X-ray crystal structures of the ternary complexes 3-thrombin-hirugen and 4-thrombin-hirugen depict novel interactions in the S1′ region, with the benzothiazole ring forming a hydrogen bond with His-57 and an aromatic stacking interaction with Trp-60D of thrombin's insertion loop. The benzothiazole ring of 3 displaces the Lys-60F side chain into a U-shaped gauche conformation, whereas the benzothiazole carboxylate of 4 forms a salt bridge with the side chain of Lys-60F such that it adopts an extended anti conformation. Since 3 has a 10-fold greater affinity for thrombin than does 4, any increase in binding energy resulting from this salt bridge is apparently offset by perturbations across the enzyme (viz. Figure 4). The increased affinity and selectivity of 2-ketobenzothiazole inhibitors, such as 3, may be primarily due to the aromatic stacking interaction with Trp-60D. However, energy contour calculations with the computer program GRID also indicate a favorable interaction between the benzothiazole sulfur atom and a hydrophobic patch on the surface of thrombin.

Molecular design and structure - Activity relationships leading to the potent, selective, and orally active thrombin active site inhibitor BMS-189664

A series of structurally novel small molecule inhibitors of human α-thrombin was prepared to elucidate their structure-activity relationships (SARs), selectivity and activity in vivo. BMS-189664 (3) is identified as a potent, selective, and orally active reversible inhibitor of human α-thrombin which is efficacious in vivo in a mouse lethality model, and at inhibiting both arterial and venous thrombosis in cynomolgus monkey models.

THROMBIN INHIBITORS

The invention relates to non-slow-binding thrombin inhibitors of the formula: A-B-C-Lys-D wherein A is H, 2-hydroxy-3-cyclohexyl-propionyl-, R1, R1—O—CO—, R1—SO2—, —(CHR2)nCOOR3, or an N-protecting group, wherein R1 is selected from -(1-6C)alkylene-COOH, (1-12C)alkenyl, (6-14C)aryl, (7-15C)aralkyl and (8-16C)aralkenyl, the group of which may be substituted with (1-6C)alkyl, (2-12C)alkoxy, hydroxy, or halogen; R2 is H or has the same meaning as R1, R3 is selected from H, (112C)alkyl, (2-12C)alkenyl, (6-14C)aryl, (7-15C)aralkyl and (8-16C)aralkenyl, the aryl group of which may be substituted with (1-6C)alkyl, (2-12C)alkoxy, hydroxy or halogen; n is an integer of 1 to 3; B is a bond, L-Asp or an derivative thereof, Leu,norLeu, -n(benzyl)—CH2—CO—, -N(2-indane)—CH2—CO—, D-1Piq, D-Tiq, Atc or a D-amino acid having a hydrophobic aromatic side chain; C is Azt, Pro, Pec, norLeu(cyclo)Gly, an amino acid of one of the formulae -N[(3-8C)cycloalkyl]—CH—CO—or -N(benzyl)—CH2—CO —, D is selected from COOH, tetrazole, oxazole,thiazole and benzothiazole, or A znd C have the aforesaid meaning, B is D-(3-8C) cycloalkylalanine, and D is tetrazole, oxazole, thiazole or benzothiazole; or a prodrug thereof; or a pharmaceutically acceptable salt thereof; with the exception of the compound Me-D-Phe-Pro-Lys-COOH. The compounds can be used as antithrombotic agents.

Methods of determining endogenous thrombin potential (ETP) and thrombin substrates for use in said methods

A method for determining the endogenous thrombin potential of a sample having a total anticoagulant activity of or equivalent to at least 0.07 U ISH/ml, includes using a thrombin substrate or a salt thereof that is soluble in the sample to determine the ETP of the sample. Suitable thrombin substrate include those of the formula P-Val-Xaa-S, in which P is an amino protective group, that is non-aromatic and polar, Val is a valine residue attached via a peptide bond to Xaa, Xaa is an amino acid residue comprising a terminal guanidino group or ureido group separated by at least 2 carbon atoms from the peptide backbond the amino acid residue is attached to S and S is a signal group such as a chromophore that can be enzymatically hydrolyzed. Other substrates include substrates comprising the structure Zaa-Pipecolyl-Yaa-S or Zaa-Pro-Yaa-S, wherein Zaa represents D-Phenylalanine, D-Tryptophan or D-Tyrosine, Pro represents proline, Yaa is an amino acid residue other than arginine and S is a signal marker can also be used. The substrates Boc-Gly-Val-Arg-pNA and H-Glu-Gly-Gly-Val-Arg-pNA are also applicable. Furthermore ETP determination methods can be improved by addition of hydroxylamine to the sample to circumvent defibrination of the sample.