Metabolically stabilized agonists of luteinizing hormone-releasing hormone (LHRH)

Haviv, Fortuna; Fitzpatrick, Timothy D.; Nichols, Charles J.; Bush, Eugene N.; Diaz, Gilbert

doi:10.1007/978-94-011-2264-1_15

Cited by 3 publications

(5 citation statements)

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“…It is noteworthy that, as is indicated above, in our laboratory NalGlu (7) was more potent than SB-75 (3) in the receptor binding and LH inhibition assays (Table I). These results differ from those described in a recent publication by Rivier et al24 wherein they found SB-75 to be more potent than NalGlu in inhibiting LH in vitro by 1.56-1.0 with a range of 1.00-2.45.…”

Section: Resultssupporting

confidence: 66%

“…The HR ED50 for A-75998 (6) was 10 Mg/mL, which is 26-fold lower than antide (5), but 10-fold higher than NalGlu (7).…”

Section: Resultsmentioning

confidence: 75%

“…Again our data for antide are consistent with those reported by Ljungqvist et al 25 for the dose of 10 Mg/rat. NalGlu (7) effectively suppressed LH during the first 8 h, and only 40% of the suppression was restored by 24 h. Rivier et al24 also tested NalGlu and antide in male castrated rats using a dose of 10 Mg/rat, which is comparable to the 30 Mg/kg used by us. With both antagonists, at the 10 Mg/rat dose, they also observed LH suppression which lasted less Plasma LH levels in nanograms per milliliter following the sc administration of 30 Mg/kg of 1-7 antagonists to male castrate rats.…”

Section: Resultsmentioning

confidence: 89%

“…Effect of NMeTyr5 on in Vitro Activity. NalGlu (7) is a well-known representative of the third-generation antagonists.17 This antagonist has been tested in humans and was found to be effective in suppressing gonadotropins and sex steroids; however it suffers from side effects. While °Analytical HPLC retention time in minutes.…”

Section: Resultsmentioning

confidence: 99%

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The effect of NMeTyr5 substitution in luteinizing hormone-releasing hormone antagonists

Haviv

Fitzpatrick²,

Nichols³

et al. 1993

J. Med. Chem.

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Section: Resultssupporting

confidence: 66%

“…The HR ED50 for A-75998 (6) was 10 Mg/mL, which is 26-fold lower than antide (5), but 10-fold higher than NalGlu (7).…”

Section: Resultsmentioning

confidence: 75%

Section: Resultsmentioning

confidence: 89%

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

The effect of NMeTyr5 substitution in luteinizing hormone-releasing hormone antagonists

Haviv

Fitzpatrick²,

Nichols³

et al. 1993

J. Med. Chem.

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“…N-Methylation at the remaining positions 6, 7, 8, or 10 had no influence whatsoever (1 versus 9,10,11, and 12). Chymotrypsin has been shown to cleave the Trp3-Ser4 bond in leuprolide.8 Therefore, N-methylation of Ser4 (7) was clearly expected to stabilize this peptide bond to cleavage, since it blocks the mechanism of action of the enzyme as we already reported.7,8 More unexpected, though, was that N-methylation of the peptide bond preceding or following the 3-4 bond also stabilized it against cleavage by chymotrypsin, as dem- °Values determined by FABMS. b tn = HPLC retention time in min. '…”

Section: Resultsmentioning

confidence: 99%

Effect of N-methyl substitution of the peptide bonds in luteinizing hormone-releasing hormone agonists

Haviv

Fitzpatrick²,

Swenson³

et al. 1993

J. Med. Chem.

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Each peptide bond in leuprolide (1), deslorelin (13), and nafarelin (24) was separately substituted with N-methyl. The synthesized compounds were tested for in vitro receptor binding, LH release, and stability against chymotrypsin and intestinal degradation. The NMe-Ser4 (30), NMe-Leu7 (33), and Sar10 (35) analogues of nafarelin had pD2 values 2-, 20-, 9-fold higher than their respective parent. All the other N-methyl agonists were less active. For the first time, conversion of LHRH agonists to antagonists was observed as a result of N-methyl substitution in the peptide backbone. [NMe-Phe2,DLeu6,Pro9NHEt]LHRH (4), [NMe-1Nal3,DLeu6,Pro9NHEt]LHRH (6), [NMe-His2,DTrp6,Pro9NHEt]LHRH (14), [NMe-Phe2,DNal6]LHRH (27), and [D2Nal6,NMe-Arg8]LHRH (34) exhibited antagonist responses. Substitutions of NMe-1Nal3, NMe-Ser4, or NMe-Tyr5 in leuprolide rendered the 3-4 peptide bond in these compounds completely stable to chymotrypsin. Examination of the three-dimensional structure of leuprolide when bound to the active site of chymotrypsin, reveals the NH's of residues 3 and 5 are involved in hydrogen bond interactions with the enzyme. N-Methylation at these positions is not only disrupting the hydrogen bond interactions, but is also sterically preventing the substrate from fitting in the enzyme's active site. All the compounds in the leuprolide series were also tested against intestinal degradation using an in vitro rat jejunum sac assay. In this model the pattern of stabilization was similar, but not identical, to that against chymotrypsin. The pharmacokinetics of all the analogues in the leuprolide series and of several others in the deslorelin and nafarelin series were determined. The clearance values of all the three NMe-Tyr5 analogues, 8, 20, and 31 were lower than their respective parents. These slower clearances suggest lower rates of metabolism.

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Synthetic Approaches to Incorporation of Novel Amino Acids into Gonadotropin-Releasing Hormone Peptides

Haviv¹,

Fitzpatrick²

1993

Methods in Neurosciences

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Metabolically stabilized agonists of luteinizing hormone-releasing hormone (LHRH)

Cited by 3 publications

References 1 publication

The effect of NMeTyr5 substitution in luteinizing hormone-releasing hormone antagonists

The effect of NMeTyr5 substitution in luteinizing hormone-releasing hormone antagonists

Effect of N-methyl substitution of the peptide bonds in luteinizing hormone-releasing hormone agonists

Synthetic Approaches to Incorporation of Novel Amino Acids into Gonadotropin-Releasing Hormone Peptides

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