ChemInform Abstract: Synthesis and Biological Activity of Some Very Hydrophobic Superagonist Analogues of Luteinizing Hormone‐Releasing Hormone.

Nestor, John J.; Ho, Teck-Hua; Simpson, R.; Horner, Bonnie L.; Jones, Gordon H.; McRae, G.I.; Vickery, B. H.

doi:10.1002/chin.198249309

Cited by 5 publications

(5 citation statements)

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“…We recognized that past SAR studies in the GnRH agonist series suggested that most D-amino acids at position 6 would influence potency in vivo favorably to about the same extent, [23][24][25] and that in the antagonists series the nature of this D-amino acid substitution may have a significant effect on duration of action. 11,26 The observation made earlier that compatibility of different acylating agents of the Aph 5 and DAph 6 and more particularly of Hor is important was vindicated in that the [Aph 5 (Hor)-DAph 6 (DHor)] substitution in 41 is more favorable than the corresponding [Aph 5 (Hor)-DAph 6 (Hor)] substitution in 30.…”

Section: Resultsmentioning

confidence: 99%

GnRH Antagonists: A New Generation of Long Acting Analogues Incorporatingp-Ureido-phenylalanines at Positions 5 and 6

et al. 2000

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A series of antagonists of gonadotropin-releasing hormone (GnRH) of the general formula Ac-D2Nal-D4Cpa-D3Pal-Ser-4Aph/4Amf(P)-D4Aph/D4Amf(Q)-Leu-ILys-Pro-DAla-NH2 was synthesized, characterized, and screened for duration of inhibition of luteinizing hormone release in a castrated male rat assay. Selected analogues were tested in a reporter gene assay (IC50 and pA2) and an in vitro histamine release assay. P and Q contain urea/carbamoyl functionalities designed to increase potential intra- and intermolecular hydrogen bonding opportunities for structural stabilization and peptide/receptor interactions, respectively. These substitutions resulted in analogues with increased hydrophilicity and a lesser propensity to form gels in aqueous solution than azaline B [Ac-D2Nal-D4Cpa-D3Pal-Ser-4Aph(Atz)-D4Aph(Atz)-Leu-ILys-Pro-DAla-NH2 with Atz = 3'-amino-1H-1',2',4'-triazol-5'-yl, 5], and in some cases they resulted in a significant increase in duration of action after subcutaneous (s.c.) administration. Ac-D2Nal-D4Cpa-D3Pal-Ser-4Aph(L-hydroorotyl)-D4Aph(carbamoyl)-Leu-ILys-Pro-DAla-NH2 (acetate salt is FE200486) (31) and eight other congeners (20, 35, 37, 39, 41, 45-47) were identified that exhibited significantly longer duration of action than acyline [Ac-D2Nal-D4Cpa-D3Pal-Ser-4Aph(Ac)-D4Aph(Ac)-Leu-ILys-Pro-DAla-NH2] (6) when administered subcutaneously in castrated male rats at a dose of 50 microg in 100 microL of phosphate buffer. No correlation was found between retention times on a C18 reverse phase column using a triethylammonium phosphate buffer at pH 7.0 (a measure of hydrophilicity) or affinity in an in vitro human GnRH report gene assay (pA2) and duration of action. FE200486 was selected for preclinical studies, and some of its properties were compared to those of other clinical candidates. In the intact rat, ganirelix, abarelix, azaline B, and FE200486 inhibited plasma testosterone for 1, 1, 14, and 57 days, respectively, at 2 mg/kg s.c. in 5% mannitol (injection volume = 20 microL). Based on the information that 31, 33, 35 and 37 were significantly shorter acting than acyline or azaline B after intravenous administration (100 microg/rat), we surmised that the very long duration of action of the related FE200486 (for example) was likely due to unique physicochemical properties such as solubility in aqueous milieu, comparatively low propensity to form gels, and ability to diffuse at high concentrations in a manner similar to that described for slow release formulations of peptides. Indeed, in rats injected s.c. with FE200486 (2 mg/kg), plasmatic concentrations of FE200486 remained above 5 ng/mL until day 41, and the time after which they dropped below 3 ng/mL and plasma LH levels started rising until full recovery was reached at day 84 with levels of FE200486 hovering around 1 ng/mL. Additionally, FE200486 was less potent at releasing histamine from isolated rat mast cells than any of the GnRH antagonists presently described in preclinical reports.

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Section: Resultsmentioning

confidence: 99%

GnRH Antagonists: A New Generation of Long Acting Analogues Incorporatingp-Ureido-phenylalanines at Positions 5 and 6

et al. 2000

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“…2Nal had previously been utilized in structure/activity studies on tetragastrin and somatostatin analogs [80,81]. Subsequently was utilized in the design of superagonist LHRH analogs [82]. It may be recalled also that replacement of the Tyr 2 residue in OT and in AVP agonists with and 2Nal resulted in analogs which exhibited potent OT antagonism in vitro and in vivo in rat bioassays [45,52,53,[83][84][85].…”

Section: Introductionmentioning

confidence: 99%

Design of peptide oxytocin antagonists with strikingly higher affinities and selectivities for the human oxytocin receptor than atosiban

et al. 2005

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The peptide oxytocin (OT) antagonist atosiban, approved for tocolytic use in Europe (under the tradename Tractocile), represents an important new therapeutic advance for the treatment of premature labor. This paper presents some new peptide OT antagonists which offer promise as superior tocolytics. The solid phase synthesis is reported of four pairs of L and D-2-naphthylalanine (L/D-2Nal) position-2 modified analogs of the following four oxytocin (OT) antagonists: des-9-glycinamide [1-(beta-mercapto-beta,beta-pentamethylene propionic acid), 2-O-methyltyrosine, 4-threonine]ornithine-vasotocin (desGly-NH(2),d(CH(2))(5)[Tyr(Me)(2),Thr(4)]OVT) (A); the Tyr-NH(2) (9) analog of (A), d(CH(2))(5)[Tyr(Me)(2),Thr(4),Tyr-NH(2) (9)]OVT (B); the Eda(9) analog of (A), d(CH(2))(5)[Tyr(Me)(2),Thr(4),Eda(9)]OVT (C); and the retro COCH(2)Ph(4-0H)(10) modified analog of (C), d(CH(2))(5)[Tyr(Me)(2),Thr(4),Eda(9)<-- COCH(2)Ph(4-0H)(10)]OVT (D). The eight new analogs of A-D are (1) desGly-NH(2),d(CH(2))(5)[D-2Nal(2),Thr(4)]OVT, (2) desGly-NH(2),d(CH(2))(5)[2-Nal(2),Thr(4)]OVT, (3) d(CH(2))(5)[D-2Nal(2),Thr(4),Tyr-NH(2) (9)]OVT, (4) d(CH(2))(5)[2Nal(2),Thr(4),Tyr-NH(2) (9)]OVT, (5) d(CH(2))(5)[D-2Nal(2),Thr(4),Eda(9)]OVT, (6) d(CH(2))(5)[2Nal(2),Thr(4),Eda(9)]OVT, (7) d(CH(2))(5)[D-2Nal(2),Thr(4),Eda(9)<-- COCH(2)Ph(4-0H)(10)]OVT, (8) d(CH(2))(5)[2Nal(2),Thr(4),Eda(9)<-- COCH(2)Ph(4-OH)(10)]OVT. Peptides 1-8 were evaluated for agonistic and antagonistic activities in in vitro and in vivo rat bioassays, in rat OT receptor (rOTR) binding assays and in human OT receptor (hOTR) and human vasopressin (VP) vasopressor (V(1a)) receptor (hV(1a)R) binding assays. Also reported are the hOTR and hV(1a)R affinity data for atosiban and for B. None of the eight peptides exhibit oxytocic or vasopressor agonism. Peptides 1-8 exhibit weak antidiuretic agonism (activities in the range 0.014-0.21 U/mg). Peptides 1-6 exhibit potent in vitro (no Mg(2+)) OT antagonism (anti-OT pA(2) values range from 7.63 to 8.08). Peptides 7 and 8 are weaker OT antagonists. Peptides 1-6 are all OT antagonists in vivo (estimated in vivo anti-OT pA(2) values in the range 6.94-7.23). Peptides 1-8 exhibit vasopressor antagonism, anti-V(1a) pA(2) values in the range 5.1-7.65. Peptides 1-8 exhibit high affinities for the rOTR (K(i) values = 0.3-7.8 nM). Peptides 1-4 and B exhibit surprisingly very high affinities for the hOTR; their K(i) values are 0.17, 0.29, 0.07, 0.14 and 0.59 nM, respectively. Peptides 1-4 and B exhibit respectively 449, 263, 1091, 546 and 129 times greater affinity for the hOTR than atosiban (K(i) = 76.4 nM). Peptides 1-4 exhibit high affinities for the hV(1a)R (K(i)s = 1.1 nM, 1.3 nM, 0.19 nM and 0.54 nM, all higher than the hV1(a)R affinities exhibited by atosiban (K(i) = 5.1 nM) and by B (K(i) = 5.26 nM). Because of their strikingly higher affinities for the hOTR than atosiban, peptides 1-4 and B exhibit gains in anti hOT/anti hV(1a) receptor selectivity compared with atosiban of 93, 64, 39, 56 and 127, respectively. These OT antagonists are thus promisi...

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“…47, No. 20 4811 procedures from 3,4,5-trimethoxybenzaldehyde, 27,28 while the 3,4-dimethoxy analogue, N R -Boc-3,4-L-dimethoxyphenylalanine, was from a commercial source. The phenylalanine derivatives were coupled to a to provide the Boc-protected dipeptides.…”

Section: Lettersmentioning

confidence: 99%

Entry into a New Class of Potent Proteasome Inhibitors Having High Antiproliferative Activity by Structure-Based Design

et al. 2004

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ChemInform Abstract: Synthesis and Biological Activity of Some Very Hydrophobic Superagonist Analogues of Luteinizing Hormone‐Releasing Hormone.

Abstract: Im Peptid Glu‐His‐Trp‐Ser‐Tyr‐Gly‐ Leu‐Arg‐Pro‐Gly‐NHQ (= LH‐RH) wird die 6‐Position durch die lipophilen D‐Amino‐ säuren (I) und (V) ersetzt.

Cited by 5 publications

References 0 publications

GnRH Antagonists: A New Generation of Long Acting Analogues Incorporatingp-Ureido-phenylalanines at Positions 5 and 6

GnRH Antagonists: A New Generation of Long Acting Analogues Incorporatingp-Ureido-phenylalanines at Positions 5 and 6

Design of peptide oxytocin antagonists with strikingly higher affinities and selectivities for the human oxytocin receptor than atosiban

Entry into a New Class of Potent Proteasome Inhibitors Having High Antiproliferative Activity by Structure-Based Design

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