Factors that Restrict the Cell Permeation of Cyclic Prodrugs of an Opioid Peptide, Part 3: Synthesis of Analogs Designed to have Improved Stability to Oxidative Metabolism

Nofsinger, Rebecca; Fuchs-Knotts, Tarra; Borchardt, Ronald T.

doi:10.1002/jps.23109

Cited by 7 publications

(4 citation statements)

References 45 publications

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“…A cyclic prodrug of DADLE was synthesized by conjoining the N- and C-termini through a coumarinic acid (CA)-linker, yielding a lipophilic and uncharged cyclic peptide [94,95]. Through cell culture models, CA-DADLE was determined to be a substrate for apically polarized efflux transporters within the intestinal mucosa and falls victim to oxidative metabolism at two major positions through liver microsomes and human recombinant cytochrome P450 3A4 (hCYP3A4), Tyr 1 and Phe 4 [96–100]. In lieu of this, additional cyclic prodrugs of DADLE, CA-[Cha 4 ,DLeu 5 ]-ENK and CA-[Cha 4 ,DAla 5 ]-ENK, were synthesized to investigate what effect modification of the 4 th position has on oxidative metabolism and cell permeation [100].…”

Section: Introductionmentioning

confidence: 99%

“…Through cell culture models, CA-DADLE was determined to be a substrate for apically polarized efflux transporters within the intestinal mucosa and falls victim to oxidative metabolism at two major positions through liver microsomes and human recombinant cytochrome P450 3A4 (hCYP3A4), Tyr 1 and Phe 4 [96–100]. In lieu of this, additional cyclic prodrugs of DADLE, CA-[Cha 4 ,DLeu 5 ]-ENK and CA-[Cha 4 ,DAla 5 ]-ENK, were synthesized to investigate what effect modification of the 4 th position has on oxidative metabolism and cell permeation [100]. Cha-substituted analogues did not exhibit greater metabolic stability relative to CA-DADLE.…”

Section: Introductionmentioning

confidence: 99%

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Cyclic Opioid Peptides

Remesic

Lee

Hruby³

2016

CMC

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For decades the opioid receptors have been an attractive therapeutic target for the treatment of pain. Since the first discovery of enkephalin, approximately a dozen endogenous opioid peptides have been known to produce opioid activity and analgesia, but their therapeutics have been limited mainly due to low blood brain barrier penetration and poor resistance to proteolytic degradation. One versatile approach to overcome these drawbacks is the cyclization of linear peptides to cyclic peptides with constrained topographical structure. Compared to their linear parents, cyclic analogues exhibit better metabolic stability, lower off-target toxicity, and improved bioavailability. Extensive structure-activity relationship studies have uncovered promising compounds for the treatment of pain as well as further elucidate structural elements required for selective opioid receptor activity. The benefits that come with employing cyclization can be further enhanced through the generation of polycyclic derivatives. Opioid ligands generally have a short peptide chain and thus the realm of polycyclic peptides has yet to be explored. In this review, a brief history of designing ligands for the opioid receptors, including classic linear and cyclic ligands, is discussed along with recent approaches and successes of cyclic peptide ligands for the receptors. Various scaffolds and approaches to improve bioavailability are elaborated on and concluded with a discourse towards polycyclic peptides.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cyclic Opioid Peptides

Remesic

Lee

Hruby³

2016

CMC

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“…First, the formation of a cyclic prodrug can enhance recognition by efflux pumps as well as metabolism by cytochrome P450 enzyme. These recognition and metabolism processes have been observed in cyclic prodrugs of opioid peptides [48,52,95,97,98]. Second, the promoiety in the cyclic prodrugs can be chemically unstable during a pH change in formulation, which contributes to short shelf-life.…”

Section: Strategies For Improving Drug Transport Through the Biolomentioning

confidence: 99%

Pathways and Progress in Improving Drug Delivery Through the Intestinal Mucosa and blood–brain Barriers

et al. 2014

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One of the major hurdles in developing therapeutic agents is the difficulty in delivering drugs through the intestinal mucosa and blood-brain barriers (BBB). The goal here is to describe the general structures of the biological barriers and the strategies to enhance drug delivery across these barriers. Prodrug methods used to improve drug penetration via the transcellular pathway have been successfully developed, and some prodrugs have been used to treat patients. The use of transporters to improve absorption of some drugs (e.g., antiviral agents) has also been successful in treating patients. Other methods, including (a) blocking the efflux pumps to improve transcellular delivery and (b) modulation of cell-cell adhesion in the intercellular junctions to improve paracellular delivery across biological barriers are still in the investigational stage.

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“…This system has a cis-double bond which could facilitate the lactonization when an acyl group (R) is hydrolyzed by esterase (Scheme 1). To date, it has been used for the preparations of cyclic prodrugs of opioid peptides (5)(6)(7)(8), such as DADLE (9)(10)(11) and DADLE analogs (12), and peptidomimetics, such as an RGD (Arg-Gly-Asp) analog MK-383 (13,14). Moreover, this system was also applied in the design of non-peptide prodrugs such as meptazinol, and the prodrug of meptazinol has shown a 4-fold increase in oral bioavailability (15).…”

Section: Introductionmentioning

confidence: 99%