New Renin Inhibitors with Pseudodipeptidic Units in P1-P1' and P2'-P3' Positions.

Paruszewski, Ryszard; Jaworski, Paweł; Winiecka, Iwona; Tautt, J; Dudkiewicz, J.

doi:10.1248/cpb.50.850

Cited by 8 publications

(11 citation statements)

References 17 publications

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“…13) Coupling Reaction with DCCI/HOBt The coupling was performed by fragment condensation as shown in schemata 1-4, performed in a commonly used manner described earlier. 11,12) …”

Section: Methodsmentioning

confidence: 99%

“…[10][11][12] Between them are compounds with pseudodipeptidic units at P 1 -P 1 Ј as well at P 2 Ј-P 3 Ј positions and activity in vitro in the limits of 10 Ϫ5 M/l. 12) Other previously obtained inhibitors with eAhx ethylamide 11) or eAhxisoamylamide 13) also at the P 2 Ј-P 3 Ј positions showed inhibitory activity at a concentration of 10 Ϫ5 M/l. On the other hand, substitution of only an isoamylamide group at this position produces an inactive compound.…”

mentioning

confidence: 99%

“…Biochemical Assays. Determination of Inhibitor Stability Stability was determined as described earlier 12) against chymotrypsin in a solution of ammonium carbonate (pH 6.9) after incubation for 4 h at 37°C. Analysis of incubates was carried out by HPLC.…”

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confidence: 99%

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New Renin Inhibitors Containing Pseudodipeptidic Units in P3-P2 and P1-P1' Positions

Paruszewski

Jaworski

Bodnar

et al. 2005

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…13) Coupling Reaction with DCCI/HOBt The coupling was performed by fragment condensation as shown in schemata 1-4, performed in a commonly used manner described earlier. 11,12) …”

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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New Renin Inhibitors Containing Pseudodipeptidic Units in P3-P2 and P1-P1' Positions

Paruszewski

Jaworski

Bodnar

et al. 2005

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…The oily residue was dissolved in ethyl ether (20 ml) and washed with 20 ml portions of 2 M HCl, saturated NaHCO 3 solution and saturated NaCl solution. The ethereal solution was dried with anhydrous MgSO 4 and concentrated in vacuo. The obtained product was purified by CC.…”

Section: Methodsmentioning

confidence: 99%

Amino Acid Derivatives with Anticonvulsant Activity.

Paruszewski¹,

Strupińska²,

Stables³

et al. 2001

CHEMICAL & PHARMACEUTICAL BULLETIN

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In previous papers [1][2][3] we reported the syntheses, pharmacological evaluation and classification of series of aromatic amides of N-alkylated and N-acylated amino acids, according to the Anticonvulsant Screening Project (ASP). All of them, with one exception, were derivatives of linear amino acids. This exception was (R)-acetylproline benzylamide ((R)-Ac-Pro-BZA), which has been demonstrated as effective in mice against the maximal electroshock seizure (MES) ED 50 ϭ 67.4 mg/kg body weight (b.w.), against the subcutaneous pentylenetetrazol (sc PTZ) ED 50 ϭ183.8 mg/kg b.w., the rotarod neurotoxicity (Tox) TD 50 ϭ303.8 mg/kg b.w. and the protective index (PI), (MES)ϭ4.5.2) This strong anticonvulsant activity of proline benzylamide, as well as the cyclic structure of many antiepileptic drugs, caused us to focus attention on cyclic amino acid derivatives. Therefore, we have now designed structures of derivatives of nine of this type amino acids. The calculated log P value of the partition coefficient between n-octanol and water (log P) of five compounds (2, 5, 7, 11, 14) was moderate and we thus presumed their high activity. According to our observation, aromatic amides of N-alkylated or N-acylated amino acids of a mean hydrophobicity show strong anticonvulsant activity. 4) Too low or too high a log P value of three other compounds (4, 10, 15) could suggest the lack of activity. However, they were synthesized to verify our hypothesis, that it is possible to predict activity of this class of compounds on the basis of their hydrophobicity. This hypothesis could be right if the anticonvulsant effect was exerted by unmetabolized compounds. Hydrophobicity has no meaning if metabolites are involved in the effect. However, strong but short lasting activity seems to suggest that the unmetabolized compound is the acting one. Compound 9 was synthesized to confirm our observation that anticonvulsant activity demands the presence of amide nitrogen. Taurine (Tau) derivative (16) was synthesized because Tau is present in the brain in a significant concentration, though its function is not yet clear. It has been reported that Tau and growth factors protect the brain against excitotoxicity.5) It is supposed that Tau acts on excitatory amino acid (EAA) receptors and therefore it would be worth to obtain and the pharmacological properties of taurine benzylamide, a potential EAA receptor antagonist with anticonvulsant activity.Chemistry Syntheses were carried out as follows: General methods of synthesis, as well as untypical proceedings are given in the Experimental part. All the products were purified by crystallization or column chromatography (CC) and characterized by TLC, HPLC, 1 H-NMR, elemental analysis, and if necessary, by optical rotation determination. Physical and analytical data of the synthesized compounds are given in Tables 1 and 2

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“…[85][86][87] The application of the concept of transition-state mimetics has revolutionized the organic chemistry of renin inhibition. In fact, potent and specific lower-molecularweight substrate analogue inhibitors have been synthesized as tetrapeptides, 72,88 tripeptides, 70,71 dipeptides, 65,89 pseudopeptides, 90 and even nonpeptidic compounds. 91,92 Specifically, the recent structure-based design of aliskiren, a nonpeptide, small molecule, transition-state mimetic human renin inhibitor represents the first in a novel class of renin inhibitors discovered with the aid of molecular modeling.…”

Section: Table 1 Classes Of Renin Inhibitorsmentioning

confidence: 99%

Direct Inhibition of Renin as a Cardiovascular Pharmacotherapy

Sepehrdad¹,

Frishman²,

Stier³

et al. 2007

Cardiology in Review

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The important role of renin-angiotensin-aldosterone system blockade in the treatment of systemic hypertension, heart failure, diabetic kidney disease, and atherogenesis has been clearly established. The theoretical therapeutic advantages for inhibiting the detrimental effects of the renin-angiotensin system at its most upstream point have served as the impetus for the development of renin inhibitors. The advent of aliskiren, the first in a novel class of orally active, nonpeptide, highly specific, human renin inhibitors, provides a new modality in the armamentarium of renin-angiotensin system antagonists. Studies in marmosets and rats demonstrated that aliskiren reduced blood pressure in a dose-dependent manner and is highly efficacious in blocking plasma renin activity with parallel reductions in the levels of the other downstream constituents of the renin-angiotensin system. Clinical trials in hypertensive patients have confirmed these benefits with aliskiren whose blood pressure-lowering efficacy is similar to or better than those of standard therapeutic doses of enalapril, losartan, irbesartan, and hydrochlorothiazide. Aliskiren is well tolerated, with few reported adverse effects even at the highest doses tested. Given the established beneficial effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in the treatment of cardiovascular and renovascular diseases, future studies may further elucidate a similar protective role for aliskiren both as a monotherapy and as part of a combination therapy.

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New Renin Inhibitors with Pseudodipeptidic Units in P1-P1' and P2'-P3' Positions.

Cited by 8 publications

References 17 publications

New Renin Inhibitors Containing Pseudodipeptidic Units in P3-P2 and P1-P1' Positions

New Renin Inhibitors Containing Pseudodipeptidic Units in P3-P2 and P1-P1' Positions

Amino Acid Derivatives with Anticonvulsant Activity.

Direct Inhibition of Renin as a Cardiovascular Pharmacotherapy

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