136554-62-6Relevant articles and documents
Michael Acceptor-Based Peptidomimetic Inhibitor of Main Protease from Porcine Epidemic Diarrhea Virus
Wang, Fenghua,Chen, Cheng,Yang, Kailin,Xu, Yang,Liu, Xiaomei,Gao, Fan,Liu, He,Chen, Xia,Zhao, Qi,Liu, Xiang,Cai, Yan,Yang, Haitao
, p. 3212 - 3216 (2017/04/21)
Porcine epidemic diarrhea virus (PEDV) causes high mortality in pigs. PEDV main protease (Mpro) plays an essential role in viral replication. We solved the structure of PEDV Mpro complexed with peptidomimetic inhibitor N3 carrying a Michael acceptor warhead, revealing atomic level interactions. We further designed a series of 17 inhibitors with altered side groups. Inhibitors M2 and M17 demonstrated enhanced specificity against PEDV Mpro. These compounds have potential as future therapeutics to combat PEDV infection.
Structure-activity relationships of cyclic pentapeptide endothelin A receptor antagonists
Fukami,Nagase,Fujita,Hayama,Niiyama,Mase,Nakajima,Fukuroda,Saeki,Nishikibe,Ihara,Yano,Ishikawa
, p. 4309 - 4324 (2007/10/03)
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.
The Steric Hindrance of the Stepwise Reaction of N-Carboxy α-Amino Acid Anhydride with the α-Amino Acid Ester
Oya, Masanao,Takahashi, Tomoko
, p. 2705 - 2707 (2007/10/02)
The mechanisms of the reactions of 4-alkyloxazolidinediones (1) (N-carboxy α-amino acid anhydrides(NCAs)) with α-amino acid benzyl ester p-toluenesulfonates (2) were investigated in acetonitrile containing triethylamine at low and room temperatures.Two types of reactions were observed: (1) the polymerization of NCAs was initiated with a small amount of 2 to produce polypeptides (6), and (2) the dipeptide benzyl esters (4) were produced by the stepwise reaction of NCAs with the esters.Both the polymerization and the dipeptide formation (1+2) seemed to be initiated by the nucleophilic attack of the amino group of the ester on the C-5 carbon of NCAs.The polymerization proceeded when the side chains of the amino acid esters (R2) were more bulky than those of the NCAs (R1).On the contrary, dipeptide esters were produced when the side chains of the NCAs (R1) were more bulky than those of the esters (R2).
