136554-90-0

Upstream product

• 79-22-1 methyl chloroformate 
• 126090-33-3 (R)-2-tert-Butoxycarbonylamino-3-(1H-indol-3-yl)-propionic acid benzyl ester 
• 616-38-6 carbonic acid dimethyl ester 
• 100-51-6 benzyl alcohol 
• 5241-64-5 Boc-D-Trp-OH 

Downstream Products

• 1026578-77-7 3-[(R)-2-((R)-1-Benzyloxycarbonylmethyl-2-{(S)-2-[(R)-1-((S)-1-carboxy-3-methyl-butylcarbamoyl)-2-methyl-propylcarbamoyl]-pyrrolidin-1-yl}-2-oxo-ethylcarbamoyl)-2-tert-butoxycarbonylamino-ethyl]-indole-1-carboxylic acid methyl ester 
• 1026288-74-3 H-D-Trp(Nⁱⁿ-COOMe)-D-Asp(OBzl)-Pro-D-Val-Leu-OH 
• 173326-37-9 N-cis-2,6-dimethylpiperidinocarbonyl-γ-methylleucyl-D-1-(methoxycarbonyl)tryptophanyl-D-norleucine 
• 158740-89-7 N-(cis-2,6-dimethylpiperidinocarbonyl)-γ-methylleucyl-D-1-(methoxycarbonyl)tryptophan benzyl ester 

Relevant academic research and scientific papers

An efficient preparation of the pseudopeptide endothelin-B receptor selective antagonist BQ-788

The endothelins are a family of bicyclic 21 amino acid peptides that are potent and prolonged vasoconstrictors. BQ-788 is a modified tripeptide that is the only known highly potent and selective antagonist for the endothelin-B (ET(B)) receptor subtype discovered to date. Previous preparations of BQ-788 (N-(cis-2,6-dimethylpiperidinocarbonyl)-γ-methylleucyl-D-1-(methoxyca rbonyl)tryptophanyl-D-norleucine sodium salt) have suffered from several synthetic difficulties, including formation of the sterically hindered N-(cis-2,6-dimethylpiperidinocarbonyl)-γ-methylleucine, racemization of tryptophan during carbamination, and the facile reduction of the indole ring of tryptophan during catalytic hydrogenation. In order to prepare sufficient quantities of BQ-788 for in vitro and in vivo evaluations of the physiological significance of the ET(B) receptor, we have developed an efficient solution phase multiple-gram synthetic strategy.

Structure-activity relationships of cyclic pentapeptide endothelin A receptor antagonists

Analogues of the natural product endothelin A (ET(A)) receptor antagonists cyclo(-D-Trp1-D-Glu2-Ala3-D-Va14-Leu5-) (1) and cyclo(-D-Trp1-D-Glu2- Ala3-D-alloIle4-Leu5-) (2) were prepared and tested for inhibitory activity against [125I]endothelin (ET-1) binding to protein ET(A) receptors. The DDLDL chirality sequence of the natural products appeared to be critical for inhibitory activity because conversion of either D-Trp or D- Glu (or both) in 1 to the corresponding L-isomer(s) abolished this property. Systematic modifications at each position of the natural products clarified the structure-activity relationships and led to highly potent and selective ET(A) receptor antagonists. Most replacements of D-Trp1 and Leu5 with other amino acids caused a significant loss of inhibitory activity. In contrast, replacement of D-Glu2 with D-Asp2 enhanced the activity. With regard to the Ala3 position, all analogues with imino acids, independent of being cyclic or acyclic, showed higher affinities than did the amino acid analogues. In addition, most replacements with amino acids, which had various functional groups in their side chains, did not significantly modify ET(A) binding affinity. The D-Va14/D-alloIle4 position was very important for inhibitory activity, and a β-position branched D-amino acid or a D-heteroarylglycine was preferable at this position. Among synthesized cyclic pentapeptides, compound 36 (BQ-518) was the most potent ETA receptor antagonist, with a pA2 of 8.1 against ET-1-induced vasoconstriction in isolated porcine coronary arteries. This compound also showed the greatest selectivity between ET(A) and ET(B) receptors (IC50 for human ET(A) = 1.2 nM, IC50 for human ET(B) = 55 μM). In contrast, compound 8 (BQ-123) is a highly soluble, potent, and selective ET(A) receptor antagonist (pA2 = 7.4, IC50 for human ET(A) = 8.3 nM, IC50 for human ET(B) = 61 μM). The sodium salt of 8 is practically freely soluble in saline. These compounds are useful tools for not only in vitro but also in vivo pharmacological studies.