Dual metalloprotease inhibitors. II. Effect of substitution and stereochemistry on benzazepinone based mercaptoacetyls

Robl, Jeffrey A.; Simpkins, Ligaya M.; Sulsky, Richard; Sieber-McMaster, Ellen; Stevenson, Jay; Kelly, Yolanda F.; Sun, Chuanyu; Misra, Raj N.; Ryono, Denis E.; Asaad, Magdi M.; Bird, J. E.; Trippodo, N. C.; Karanewsky, Donald S.

doi:10.1016/s0960-894x(01)80373-5

Cited by 26 publications

(23 citation statements)

References 14 publications

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“…Cheminformatic analysis indicates that the tandem ODRE library overlaps with medium‐ring natural products and is distinct from conventional synthetic drugs and drug‐like libraries, accessing regions of chemical space that are underrepresented in probe and drug discovery. Notably, related benzannulated medium‐ring lactam scaffolds have also been used in structure‐based designed of angiotensin‐converting enzyme inhibitors . While the immediate applications of these molecules lie in efforts to discover novel biological probes, both β‐ketolactam and N ‐alkoxyamide motifs are found in approved and investigational drugs, suggesting that these motifs are also compatible with eventual translational applications .…”

Section: Discussionmentioning

confidence: 99%

Synthesis of Benzannulated Medium‐ring Lactams via a Tandem Oxidative Dearomatization‐Ring Expansion Reaction

Guney

Wenderski

Boudreau

et al. 2018

Chemistry A European J

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Medium-ring natural products exhibit diverse biological activities but such scaffolds are underrepresented in probe and drug discovery efforts due to the limitations of classical macrocyclization reactions. We report herein a tandem oxidative dearomatization-ring-expanding rearomatization (ODRE) reaction that generates benzannulated medium-ring lactams directly from simple bicyclic substrates. The reaction accommodates diverse aryl substrates (haloarenes, aryl ethers, aryl amides, heterocycles) and strategic incorporation of a bridgehead alcohol generates a versatile ketone moiety in the products amenable to downstream modifications. Cheminformatic analysis indicates that these medium rings access regions of chemical space that overlap with related natural products and are distinct from synthetic drugs, setting the stage for their use in discovery screening against novel biological targets.

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Section: Discussionmentioning

confidence: 99%

Synthesis of Benzannulated Medium‐ring Lactams via a Tandem Oxidative Dearomatization‐Ring Expansion Reaction

Guney

Wenderski

Boudreau

et al. 2018

Chemistry A European J

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“…Robl and co-workers at Bristol-Myers Squibb published several series of benzo-fused Freidinger lactams 41 as conformationally restricted mimetics of mercaptoacetyl-AlaPro (40) possessing dual ACE/NEP inhibitory properties [42][43][44][45]. The group also investigated conformationally constrained bicyclic [44,46] and even tricyclic dipeptide mimetics [46,47] which led to the discovery of omapatrilat BMS-186716; (42), a potent ACE/NEP inhibitor [47].…”

Section: Angiotensin Converting Enzyme (Ace) and Neutral Endopeptimentioning

confidence: 99%

The Application of Freidinger Lactams and their Analogs in the Design of Conformationally Constrained Peptidomimetics

Perdih¹,

Kikelj

2006

CMC

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Peptides exist in solution as an equilibrium mixture of conformers. The backbone conformational constraints are of interest as a means of limiting degrees of freedom and thereby constraining a synthetic peptide into the bioactive conformation. This concept plays an important role in the design of peptidomimetics in the drug development process. In the early eighties, Freidinger proposed the concept of protected lactam-bridged dipeptides, which was a milestone in the design of conformationally constrained peptides. These types of compounds, now widely known as Freidinger lactams, have been of interest to many medicinal and peptide chemists. This review seeks to present the various applications that Freidinger lactams and their hetero-, fused- and unsaturated analogs have found in the design of conformationally constrained peptidomimetics in different therapeutic areas.

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“…Em 1993, a unidade de restrição do tipo 1,4-oxazepínico foi produzida com o objetivo de se obter análogos de inibidores da ECA, bem como da atriopeptidase (NEP) 51 . Em seguida, várias séries de derivados do tipo 42 (Figura 12), análogos dos inibidores de metaloproteases (ECA/NEP) [52][53][54]…”

Section: Inibidores Duplos De Metaloproteasesunclassified

“…Os compostos do tipo 49 mostraram um aumento da atividade e da seletividade inibidora de protease em relação às referências 50 e 51 61 . [52][53][54] .…”

Section: Inibidores Da Elastase De Leucócitos Humanosunclassified

Peptídeos de conformação restrita induzida pela incorporação de unidades (aza)lactâmicas

Pohlmann¹,

Quirion²,

Guillaume³

et al. 1999

Quím. Nova

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Recebido em 21/8/98; aceito em 29/1/99 CONFORMATIONALLY CONSTRAINED INDUCED PEPTIDES CONTAINING (AZA)LACTAM UNITS. Conformational constraint is an approach which can be used to restrict the flexibility of peptide molecules and to provide information on the topographical requirements of receptors. The incorporation of conformationally constrained units in a peptide can lead to peptide analogues that present numerous advantages such as the potentialization of the pharmacological activity and the decrease of enzymatic degradation. This review discusses the peptide analogues containing a lactam or azalactam unit in their sequences. Of particular interest has been the replacement of a dipeptide motif in a peptide that simulates a β-turn.

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Dual metalloprotease inhibitors. II. Effect of substitution and stereochemistry on benzazepinone based mercaptoacetyls

Cited by 26 publications

References 14 publications

Synthesis of Benzannulated Medium‐ring Lactams via a Tandem Oxidative Dearomatization‐Ring Expansion Reaction

Synthesis of Benzannulated Medium‐ring Lactams via a Tandem Oxidative Dearomatization‐Ring Expansion Reaction

The Application of Freidinger Lactams and their Analogs in the Design of Conformationally Constrained Peptidomimetics

Peptídeos de conformação restrita induzida pela incorporação de unidades (aza)lactâmicas

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