Design and synthesis of a potent and specific renin inhibitor with a prolonged duration of action in vivo

Thaisrivongs, Suvit; Pals, Donald T.; Harris, Douglas W.; Kati, Warren M.; Turner, Steve R.

doi:10.1021/jm00160a049

Cited by 57 publications

(22 citation statements)

References 5 publications

(14 reference statements)

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“…In contrast, the lactonization reaction proceeds much more quickly with the Gln HE systems and for the TBS silyl ether HE analog 3; over 20% (24). Nevertheless, several HE derivatives have been synthesized and deprotected without lactonizationfragmentation being described (12,25,26).…”

Section: Resultssupporting

confidence: 90%

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Facile degradative lactonization of Gln‐Arg and Gln‐Phe hydroxyethylene dipeptide derivatives*

Haug

Brewer

Rich

2005

The Journal of Peptide Research

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Section: Resultssupporting

confidence: 90%

“…(15) and to a lactone byproduct formed via acidic deprotection of a Leu‐Ala HE dipeptide derivative (24). Nevertheless, several HE derivatives have been synthesized and deprotected without lactonization‐fragmentation being described (12,25,26).…”

Section: Resultsmentioning

confidence: 99%

Facile degradative lactonization of Gln‐Arg and Gln‐Phe hydroxyethylene dipeptide derivatives*

Haug

Brewer

Rich

2005

The Journal of Peptide Research

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“…This strategy differs from the common feature pharmacophore approach in various points such as limitations of number of training set compounds and necessity of experimental activity values predicted using similar bioassay conditions etc [13]. More than 300 chemical compounds were retrieved from various literature resources [14-19] and 111 compounds evaluated with the same bio-assay protocol were selected to be used as primary data set in 3D QSAR pharmacophore modeling study. To ensure the statistical relevance, a training set containing 18 diverse compounds with the experimental activity values (IC 50 ) ranging from 0.5 nM to 5590 nM were selected from 111 dataset compounds and used as training set (Figure 1) and the remaining 93 compounds were used as test set compounds to be utilized in pharmacophore validation.…”

Section: Methodsmentioning

confidence: 99%

Development, evaluation and application of 3D QSAR Pharmacophore model in the discovery of potential human renin inhibitors

et al. 2011

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BackgroundRenin has become an attractive target in controlling hypertension because of the high specificity towards its only substrate, angiotensinogen. The conversion of angiotensinogen to angiotensin I is the first and rate-limiting step of renin-angiotensin system and thus designing inhibitors to block this step is focused in this study.MethodsLigand-based quantitative pharmacophore modeling methodology was used in identifying the important molecular chemical features present in the set of already known active compounds and the missing features from the set of inactive compounds. A training set containing 18 compounds including active and inactive compounds with a substantial degree of diversity was used in developing the pharmacophore models. A test set containing 93 compounds, Fischer randomization, and leave-one-out methods were used in the validation of the pharmacophore model. Database screening was performed using the best pharmacophore model as a 3D structural query. Molecular docking and density functional theory calculations were used to select the hit compounds with strong molecular interactions and favorable electronic features.ResultsThe best quantitative pharmacophore model selected was made of one hydrophobic, one hydrogen bond donor, and two hydrogen bond acceptor features with high a correlation value of 0.944. Upon validation using an external test set of 93 compounds, Fischer randomization, and leave-one-out methods, this model was used in database screening to identify chemical compounds containing the identified pharmacophoric features. Molecular docking and density functional theory studies have confirmed that the identified hits possess the essential binding characteristics and electronic properties of potent inhibitors.ConclusionA quantitative pharmacophore model of predictive ability was developed with essential molecular features of a potent renin inhibitor. Using this pharmacophore model, two potential inhibitory leads were identified to be used in designing novel and future renin inhibitors as antihypertensive drugs.

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“…Proline, D-phenylalanine, lysine and glutamic acid substantially reduce potency when incorporated at Pa, 'l3,l7* as does (C*-methy1)phenylalanine. 129 The amino acids (Nu-nitro)arginine and (N"-cyano)homoarginine, and acylated analogs of lysine have been incorporated at the P2 position of potent inhibitors. 175 An inhibitor (17-3) with a potency-enhancing (1,3-dioxolan-2-y1)methyl substituent at P2 has been reported (Table XVII).17'j Histidine in inhibitor 15-10 may be replaced with (N"-methyl)histidine, but (W- EtOC-Phe-His-ACHPA-NH-2(S)-MeBu E tOC-Phe-Leu-ACHPA-NH-2(S)-MeBu EtOC- Phe-[ 1,3-dioxolan-2-yI) Table I footnotes.…”

Section: G Amino-terminal Modifications P2 Amino Acidsmentioning

confidence: 99%

Renin inhibitors

Greenlee

1990

Medicinal Research Reviews

284

139

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Since the early 1980s, an intensive effort has been focused on the development of orally effective and long-acting inhibitors of renin. During this time, in vitro potency has increased greatly, with several transition-state inhibitor designs yielding inhibitors with subnanomolar IC50 values. In the meantime, both the molecular weight and peptide character of the inhibitors has decreased as important binding elements have been focused into smaller and more stable structures. The resulting inhibitors have shown promising activities in several in vivo models and (in two cases) in man. Nevertheless, renin inhibitors reported to date have limited oral bioavailability and short duration of action, and improvements in both will be necessary for them to compete effectively with ACE inhibitors. Renin inhibitors which have entered clinical studies have at least one naturally occurring amino acid and three or more amide bonds. It is reasonable to expect that continued development will produce wholly nonpeptide inhibitors with still lower MW, and it may be these "second-generation" inhibitors which will succeed as therapeutic agents. Development of orally effective and long-acting inhibitors of renin will enable their long-term antihypertensive efficacy and possible advantages over ACE inhibitor to be investigated.

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Design and synthesis of a potent and specific renin inhibitor with a prolonged duration of action in vivo

Cited by 57 publications

References 5 publications

Facile degradative lactonization of Gln‐Arg and Gln‐Phe hydroxyethylene dipeptide derivatives*

Facile degradative lactonization of Gln‐Arg and Gln‐Phe hydroxyethylene dipeptide derivatives*

Development, evaluation and application of 3D QSAR Pharmacophore model in the discovery of potential human renin inhibitors

Renin inhibitors

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