Cyclic hexapeptide oxytocin antagonists. Potency-, selectivity-, and solubility-enhancing modifications

Rm, Freidinger; Pd, Williams; Rd, Tung; Mg, Bock; Dj, Pettibone; Bv, Clineschmidt; Rm, DiPardo; Jm, Erb; Vm, Garsky; Np, Gould

doi:10.1021/jm00169a001

Cited by 25 publications

(3 citation statements)

References 4 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The peptide oxytocin antagonists cited above, for example, are iv agents with short in vivo lifetimes.1-10'11 Structural constraints such as cyclization can sometimes improve in vivo duration, as has been accomplished in the oxytocin field with cyclic hexapeptide OT antagonists, such as L-365,209. [27][28][29][30][31] The problem of oral bioavailability, however, is seldom overcome in the peptide manifold. As a consequence, we concentrated our search for an orally bioavailable OT antagonist around the nonpeptide L-342,643 (11), a screening lead with 4 µ affinity for rat uterine oxytocin receptors (Table I).…”

Section: Resultsmentioning

confidence: 99%

Orally active, nonpeptide oxytocin antagonists

Evans¹,

Leighton²,

Rittle³

et al. 1992

J. Med. Chem.

Self Cite

View full text Add to dashboard Cite

show abstract

Section: Resultsmentioning

confidence: 99%

Orally active, nonpeptide oxytocin antagonists

Evans¹,

Leighton²,

Rittle³

et al. 1992

J. Med. Chem.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Intravenous administration of 22 to anaesthetized rats antagonized the action of exogenous OT on the uterus with an AD 50 value of 0.46mg/kg and a relatively long duration of action. Encouraged by these results, a systematic lead optimisation program was initiated, with the main objectives of attaining oral bioavailability, as well as sufficient aqueous solubility for intravenous formulation [254,255,256]. Indeed, a number of more potent, selective and soluble analogues were obtained, exemplified by L-366,670 (23) and L-366,948 (24), and the latter compound was shown to be highly efficacious in reducing uterine contractions in rats (AD 50 0.10mg/kg) and rhesus monkeys by iv and sc routes [257,258].…”

Section: Peptide Antagonistsmentioning

confidence: 99%

Preterm Labour: An Overview of Current and Emerging Therapeutics

Schwarz¹,

Page²

2003

CMC

View full text Add to dashboard Cite

Preterm labour is a major cause of perinatal mortality and morbidity. However, during the past 40 years of clinical studies and despite the use of multiple therapeutic agents, the rate of preterm birth has not drastically declined. In 1991, it was estimated that in the US approximately 116,000 women admitted with acute episodes of preterm labour were treated each year with ritodrine, which is the first drug approved by the US FDA and still remains the standard therapy for treating preterm labour. Ritodrine (Yutopar( trade mark )) stimulates the beta(2)-adrenergic receptor throughout the body, causing an inhibitory action in different tissues that, among other side effects, also leads to an attenuation of uterine contractility. More recently, a new therapeutic agent, atosiban (Tractocile( trade mark )), a peptidic oxytocin receptor antagonist, has been introduced to the market. However, the use of the various pharmacological agents to treat preterm labour remains restricted, due to lack of uterine selectivity, low efficacy and potentially serious side effects for the mother or the foetus. Therefore, there is an urgent need to develop drugs with myometrial selectivity that would allow long-lasting inhibition of labour and prolong pregnancy up to a stage when good foetal maturation raises the chances of survival. One of the major obstacles hampering the development of new therapeutic agents is the marked inter-species difference in terms of preterm labour physiology, which complicates the preclinical evaluation of new candidate molecules in animal models of disease. In this review, the authors will provide a comprehensive update of past, current and new approaches for the management of preterm labour, including beta(2)-adrenergic agonists, calcium channel blockers, oxytocin antagonists, prostaglandin antagonists and other potential therapeutics. For each of the therapies used today, the review will cover the mechanism of action, benefit and adverse effects, and discuss the promise and potential benefits of new emerging therapeutic agents.

show abstract

“…The macrocycle itself provides an entropic advantage in binding if the molecule is constrained in the correct conformation. The cyclic structure and N-methylation convey protease resistance and oral bioavailability, as exemplified by cyclosporin A , and a number of somatostatin and oxytocin mimics. , Additionally, the template is comprised of readily available α-hydroxy acid and N -methylamino acid subunits.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Evaluation of a Depsipeptide Mimic of Tendamistat

et al. 1997

View full text Add to dashboard Cite

The cyclic hexadepsipeptide framework of enniatin B was identified as a template matching the beta-turn tripeptide of tendamistat. The modified analog 1 was synthesized as a tendamistat mimic and compared to the acyclic derivative 2 and the tripeptide Ac-Try-Arg-Tyr-OMe. These compounds were assembled from the dimeric esters 3-5. As an inhibitor of alpha-amylase, 1 is twice as potent as 2 and comparable to the tripeptide. NMR studies of 1 reveal four conformers in equilibrium in a 50:25:15:10 ratio; the ring conformation of the major component is similar to that of the enniatin B template, with the cis geometry of the alpha-hydroxyisovaleryl-N-methylvaline amide linkage; the other conformers differ in the position or presence of the cis amide linkage.

show abstract

Cyclic hexapeptide oxytocin antagonists. Potency-, selectivity-, and solubility-enhancing modifications

Cited by 25 publications

References 4 publications

Orally active, nonpeptide oxytocin antagonists

Orally active, nonpeptide oxytocin antagonists

Preterm Labour: An Overview of Current and Emerging Therapeutics

Design, Synthesis, and Evaluation of a Depsipeptide Mimic of Tendamistat

Contact Info

Product

Resources

About