1. Studies on neurokinin antagonists. 1. The design of novel tripeptides possessing the glutaminyl-D-tryptophylphenylalanine sequence as substance P antagonists
D Hagiwara, H Miyake, H Morimoto, M Murai, T Fujii, M Matsuo J Med Chem. 1992 May 29;35(11):2015-25. doi: 10.1021/jm00089a011.
To discover a novel and low molecular weight substance P (SP) antagonist we postulated that the essential binding domain of peptide ligands was only a small portion in the whole structure. On the basis of this assumption, we selected the known octapeptide SP antagonist D-Pro-Gln-Gln-D-Trp-Phe-D-Trp-D-Trp-Phe-NH2 (1) as a lead and synthesized its fragment tripeptides which were evaluated for their activity to block 3H-SP binding on guinea pig lung membranes. The protected tripeptide N alpha-[N alpha-[N alpha-(tert-butyloxycarbonyl)-L-glutaminyl]-N1-formyl-D-tryptophyl]- L-phenylalanine benzyl ester [Boc-Gln-D-Trp(CHO)-Phe-OBzl (4a)], corresponding to the Gln-D-Trp-Phe part of 1, exhibited 7-fold potent inhibitory activity in comparison with 1. Studies on structure-activity relationships revealed that the D-tryptophan, L-phenylalanine, and benzyl ester were quite important to maintain the high binding affinity. It was also indicated that 4a antagonized the SP-induced contraction of isolated guinea pig trachea strips (IC50 = 4.7 x 10(-6) M).
2. Studies on neurokinin antagonists. 2. Design and structure-activity relationships of novel tripeptide substance P antagonists, N alpha-[N alpha-(N alpha-acetyl-L-threonyl)-N1-formyl-D-tryptophyl]-N- methyl-N-(phenylmethyl)-L-phenylalaninamide and its related compounds
D Hagiwara, H Miyake, H Morimoto, M Murai, T Fujii, M Matsuo J Med Chem. 1992 Aug 21;35(17):3184-91. doi: 10.1021/jm00095a013.
Continuing studies on the chemical modification of the previously reported novel tripeptide SP antagonist, N alpha-[N alpha-[N alpha- (tert-butyloxycarbonyl)glutaminyl]-N1-formyl-D-tryptophyl]phenylalanine benzyl ester [Boc-Gln-D-Trp-(CHO)-Phe-OBzl (1)], are described herein. We initially investigated the stability of 1 in guinea pig plasma and liver homogenate to elucidate the most labile part in the structure. It was consequently revealed that the benzyl ester part was easily hydrolyzed to produce the inactive acid analog. Thus we searched for a benzyl ester surrogate that would be more resistant to hydrolytic enzymes. This approach found an isosteric amide structure, N-methyl-N-(phenylmethyl)amide, suitable in terms of potency and stability. Subsequent modification of the amino terminal into N alpha-acetyl-L-threonine led to the most potent compound, N alpha-[N alpha-(N alpha-acetyl-L-threonyl)-N1-formyl-D-tryptophyl]-N- methyl-N-(phenylmethyl)-L-phenylalaninamide [Ac-Thr-D-Trp(CHO)-Phe-NMeBzl (5a, FR113680)]. This compound 5a potently blocked 3H-SP binding to guinea pig lung membranes with IC50 of (5.8 +/- 0.78) x 10(-9) M. In vitro, 5a inhibited SP-induced contraction of isolated guinea pig trachea strips with IC50 of 2.3 x 10(-6) M and caused no contraction when used alone in this preparation up to 3.2 x 10(-5) M. In addition 5a exhibited no effect on the contraction induced by histamine or acetylcholine. Intriguingly, it was demonstrated in vivo that 5a suppressed the SP-induced bronchoconstriction and airway edema in guinea pigs with ED50 of 0.42 mg/kg and 0.66 mg/kg, respectively, when administered intravenously.
3. Synthetic approaches to peptides containing the L-Gln-L-Val-D(S)-Dmt motif
Ghadeer A R Y Suaifan, Tawfiq Arafat, Michael D Threadgill Bioorg Med Chem. 2007 May 15;15(10):3474-88. doi: 10.1016/j.bmc.2007.03.005. Epub 2007 Mar 6.
The pseudoprolines S-Dmo (5,5-dimethyl-4-oxaproline) and R-Dmt (5,5-dimethyl-4-thiaproline) have been used to study the effects of forcing a fully cis conformation in peptides. Synthesis of peptides containing these (which have the same configuration as L-Pro) is straightforward. However, synthesis of peptides containing S-Dmt is difficult, owing to the rapid cyclisation of L-Aaa-S-Dmt amides and esters to form the corresponding diketopiperazines (DKP); thus the intermediacy of L-Aaa-S-Dmt amides and esters must be avoided in the synthetic sequence. Peptides containing the L-Gln-L-Val-D(S)-Dmt motif are particularly difficult, owing to the insolubility of coupling partners containing Gln. Introduction of Gln as N-Boc-pyroglutamate overcame the latter difficulty and the dipeptide active ester BocPygValOC(6)F(5) coupled in good yield with S-DmtOH. BocPygVal-S- DmtNH(CH(2))(2)C(6)H(4)NO(2) was converted quantitatively to BocGlnVal-S-DmtNH(CH(2))(2)C(6)H(4)NO(2) with ammonia, demonstrating the utility of this approach. Two peptide derivatives (CbzSerLysLeuGlnVal-S-DmtNH(CH(2))(2)C(6)H(4)NO(2) and CbzSerSerLysLeuGlnVal-S- DmtNH(CH(2))(2)C(6)H(4)NO(2)) were assembled, using these new methods of coupling a dipeptide acid active ester with S-DmtOH and introduction of Gln as Pyg, followed by conventional peptide couplings. The presence of the Val caused these peptides to be cleaved very slowly by prostate-specific antigen (PSA) at Leu Gln, rather than the expected Gln Val.
