Angiotensin-converting enzyme inhibitors. 2. Perhydroazepin-2-one derivatives

Yanagisawa, Hideyoshi; Ishihara, Sadao; Ando, Akiko; Kanazaki, Takuro; Miyamoto, Shuichi; Koike, Hiroyuki; Iijima, Yasuteru; Oizumi, Kiyoshi; Matsushita, Yoh‐ichi; Hata, Tadashi

doi:10.1021/jm00397a027

Cited by 48 publications

(30 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Temocaprilat was then prepared by hydrolysis in aq. NaOH as described in [11]. Their ionization constants were determined at 258 by potentiometric titration using the Sirius GlPKa apparatus (Sirius Analytical Instruments Ltd., Forest Row, East Sussex, U.K.).…”

Section: Experimental Partmentioning

confidence: 99%

See 1 more Smart Citation

Influence of Ionization State on the Activation of Temocapril by hCES1: A Molecular‐Dynamics Study

Vistoli

Pedretti

Mazzolari

et al. 2009

Chemistry & Biodiversity

View full text Add to dashboard Cite

Temocapril is a prodrug whose hydrolysis by carboxylesterase 1 (CES1) yields the active ACE inhibitor temocaprilat. This molecular-dynamics (MD) study uses a resolved structure of the human CES1 (hCES1) to investigate some mechanistic details of temocapril hydrolysis. The ionization constants of temocapril (pK1 and pK3) and temocaprilat (pK1, pK2, and pK3) were determined experimentally and computationally using commercial algorithms. The constants so obtained were in good agreement and revealed that temocapril exists mainly in three ionic forms (a cation, a zwitterion, and an anion), whereas temocaprilat exists in four major ionic forms (a cation, a zwitterion, an anion, and a dianion). All these ionic forms were used as ligands in 5-ns MS simulations. While the cationic and zwitterionic forms of temocapril were involved in an ion-pair bond with Glu255 suggestive of an inhibitor behavior, the anionic form remained in a productive interaction with the catalytic center. As for temocaprilat, its cation appeared trapped by Glu255, while its zwitterion and anion made a slow departure from the catalytic site and a partial egress from the protein. Only its dianion was effectively removed from the catalytic site and attracted to the protein surface by Lys residues. A detailed mechanism of product egress emerges from the simulations.

show abstract

Section: Experimental Partmentioning

confidence: 99%

“…, is a zwitterionic orally active, long-acting prodrug-type ACE inhibitor [11]. It is rapidly absorbed and converted exclusively to its pharmacologically active diacid metabolite, temocaprilat (Fig.…”

mentioning

confidence: 99%

Influence of Ionization State on the Activation of Temocapril by hCES1: A Molecular‐Dynamics Study

Vistoli

Pedretti

Mazzolari

et al. 2009

Chemistry & Biodiversity

View full text Add to dashboard Cite

show abstract

“…A [2,3]-Wittig rearrangement 79 is being used to approach these mimetics synthetically (Scheme 25) 'O.…”

Section: Restriction Of Thementioning

confidence: 99%

Conformationally restricted amino acids and dipeptides, (non)peptidomimetics and secondary structure mimetics

Liskamp

1994

Recl. Trav. Chim. Pays‐Bas

181

View full text Add to dashboard Cite

show abstract

“…[15] It was noteworthy that, even without acidic additives, [1,3] ligand 2 showed remarkable selectivities compared to BINAP in the hydrogenation of 15. A key intermediate for the synthesis of ACE inhibitors Benazepril and Delapril hydrochloride [14] was readily accessible via the hydrogenation of ethyl 2-oxo-4-phenylbutyrate with up to 96 % ee (Table 3, entry 10). To our best knowledge, these results represent one of the highest enantioselectivities yet achieved yet in the preparation of optically active a-hydroxy acid derivatives using direct asymmetric hydrogenations.…”

Section: Communicationmentioning

confidence: 99%

Matching and Mismatching Effects of Hybrid Chiral Biaxial Bisphosphine Ligands in Enantioselective Hydrogenation of Ketoesters

Sun

Zhou

et al. 2009

Chemistry A European J

View full text Add to dashboard Cite

Catalytic asymmetric synthesis is a significant component in modern organic chemistry. It has widely been used to produce a number of optically active compounds, from agrochemicals, to pharmaceuticals, to flavors, and fragrances as well as functional materials.[1] One of the most important methods to increase the stereoselectivity of reactions is multiple stereoselectivity (multiple stereodifferentiation, multiple asymmetric induction), when the stereochemical process proceeds under the control of more than one chiral auxiliary.[2] During the last two decades, these double stereoselective strategies have been successfully applied in a variety of reactions, such as Sharpless dihydroxylation, Michael additions, addition to allyl metals, the Reformatsky reaction, the Mukaiyama reaction, photochemical reactions, alkylation, cycloadditions and the synthesis of heteroatom compounds.[2] In contrast, catalytic systems with multiple stereogenic axial elements in chiral ligands are much less explored in transition metal catalyzed asymmetric hydrogenations. The multiple chiral elements in ligands may be situated favorably ("matched") or unfavorably ("mismatched") for stereocontrol when the catalyst interacts with a prochiral substrate. Ultimately, the matched cases may lead to dramatically higher asymmetric induction in the products, whereas the mismatched cases often result in significantly lower selectivity in hydrogenation reactions.[3] Syntheses of these molecules have facilitated a preliminary study of matching and mismatching effects, relating backbone chirality and phosphorus-based chirality with the performance of these ligands in asymmetric catalysis. The most notable achievements of catalytic systems with double asymmetric induction exist in hydrogenation chemistry, focusing primarily on rhodium or ruthenium with bidentate phosphine ligands, [4] in particular, modifications of DIOP, [5] BINAP, [6] dialkylphospholane bis(phospholane) ligands, [7] and many others.[8] As reported, configurational changes in ligands brought by introducing additional chirality are generally unpredictable. There are no reliable predictive models to explain the structural subtleties of catalysts with multiple chiral elements that lead to dramatic changes in stereoselectivities. [9] As part of our continued interest in the synthesis and use of new chiral bisphosphine ligands in asymmetric catalysis, we have developed a novel class of conformationally rigid C n -TunePhos (n = 1-6) by introducing a bridge with variable length to link the chiral atropisometic biaryl groups.[10] This family of TunePhos ligands has proven to be highly efficient in a variety of asymmetric reactions.[11] We envision that changes of relatively flexible alkyl linker in the C n -TunePhos family with an aromatic group or a bulky chiral bridge may enhance the rigidity and steric hindrance of the structure. Consequently, unique steric or electronic effects and good chiral discrimination could be expected. Herein we report a convenient strategy for the synthesis of ...

show abstract

Angiotensin-converting enzyme inhibitors. 2. Perhydroazepin-2-one derivatives

Cited by 48 publications

References 0 publications

Influence of Ionization State on the Activation of Temocapril by hCES1: A Molecular‐Dynamics Study

Influence of Ionization State on the Activation of Temocapril by hCES1: A Molecular‐Dynamics Study

Conformationally restricted amino acids and dipeptides, (non)peptidomimetics and secondary structure mimetics

Matching and Mismatching Effects of Hybrid Chiral Biaxial Bisphosphine Ligands in Enantioselective Hydrogenation of Ketoesters

Contact Info

Product

Resources

About