Potent macrocyclic antagonists to the motilin receptor presenting novel unnatural amino acids

Marsault, Éric; Benakli, Kamel; Beaubien, Sylvie; Saint-Louis, Carl Jacky; Déziel, Robert; Fraser, Graeme L.

doi:10.1016/j.bmcl.2007.05.043

Cited by 31 publications

(18 citation statements)

References 24 publications

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“…compound 10 , Figure 4B). Further optimization through incorporation of unnatural amino acids produced potent, biologically active macrocycles in ex vivo assays [66,67]. Screening of Tranzyme’s proprietary libraries also produced a clinical candidate, TZP-101 (compound 11 , Figure 4B), as a ghrelin receptor antagonist [68].…”

Section: Methods For Discovery Of Macrocyclic Ppi Inhibitorsmentioning

confidence: 99%

Macrocycles as protein–protein interaction inhibitors

Dougherty

Qian

Pei

2017

Biochemical Journal

141

107

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Macrocyclic compounds such as cyclic peptides have emerged as a new and exciting class of drug candidates for inhibition of intracellular protein-protein interactions, which are challenging targets for conventional drug modalities (i.e. small molecules and proteins). Over the past decade, several complementary technologies have been developed to synthesize macrocycle libraries and screen them for binding to therapeutically relevant targets. Two different approaches have also been explored to increase the membrane permeability of cyclic peptides. In this review, we discuss these methods and their applications in the discovery of macrocyclic compounds against protein-protein interactions.

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Section: Methods For Discovery Of Macrocyclic Ppi Inhibitorsmentioning

confidence: 99%

Macrocycles as protein–protein interaction inhibitors

Dougherty

Qian

Pei

2017

Biochemical Journal

141

107

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“…( S )‐1‐(2‐Iodophenoxy)‐2‐propanol: 43 K 2 CO 3 (1.70 g, 12 mmol) and 2‐iodophenol (660 mg, 3 mmol) were dissolved in DMF (5 mL), and the mixture was refluxed for 1 hour. ( S )‐(–)‐Propylene oxide (240 μL, 3.3 mmol) was added and the reaction was allowed to proceed at 60 °C until completion (48 h).…”

Section: Methodsmentioning

confidence: 99%

Catalytic Enantioselective α‐Oxysulfonylation of Ketones Mediated by Iodoarenes

et al. 2008

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“…Lead optimization resulted in a series of potent motilin antagonists with IC 50 's from 1 to 20 nM. 148 Of these, TZP-201 (structure undisclosed), an advanced compound from that series, was evaluated in an irinotecan-induced diarrhea in beagle dogs. 149,150 Diarrhea was induced in male beagle dogs by intravenous bolus injection of irinotecan (6 mg kg À1 day À1 ) for two treatment cycles up to five consecutive days, separated by a 9-day wash-out period.…”

Section: Motilin Modulatorsmentioning

confidence: 99%

Macrocyclic Inhibitors of GPCR's, Integrins and Protein–Protein Interactions

Ermert

Moehle

Obrecht

2014

Macrocycles in Drug Discovery

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This chapter summarizes some highlights of macrocyclic drug discovery in the area of GPCRs, integrins, and protein–protein interactions spanning roughly the last 30 years. Several examples demonstrate that incorporation of pharmacophores derived from natural peptide ligands into the context of a constrained macrocycle (“lock of the bioactive conformation”) has proven a powerful approach for the discovery of potent and selective macrocyclic drugs. In addition, it will be shown that macrocycles, due to their semi-rigid nature, can exhibit unique properties that can be beneficially exploited by medicinal chemists. Macrocycles can adapt their conformation during binding to a flexible protein target surface (“induced fit”), and due to their size, can interact with larger protein interfaces (“hot spots”). Also, macrocycles can display favorable ADME properties well beyond the rule of 5 in particular exhibiting favorable cell penetrating properties and oral bioavailability.

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Potent macrocyclic antagonists to the motilin receptor presenting novel unnatural amino acids

Cited by 31 publications

References 24 publications

Macrocycles as protein–protein interaction inhibitors

Macrocycles as protein–protein interaction inhibitors

Catalytic Enantioselective α‐Oxysulfonylation of Ketones Mediated by Iodoarenes

Macrocyclic Inhibitors of GPCR's, Integrins and Protein–Protein Interactions

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