Investigation of the 4-O-alkylamine substituent of non-peptide quinolone GnRH receptor antagonists

DeVita, Robert J.; Goulet, Mark T.; Wyvratt, Matthew J.; Fisher, Michael H.; Lo, Jane‐L.; Yang, Yi Tien; Cheng, Kang; Smith, Roy G.

doi:10.1016/s0960-894x(99)00447-3

Cited by 51 publications

(22 citation statements)

References 9 publications

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“…Wilcoxen et al 41 confirmed the importance of the basic nitrogen and the attached benzyl group at position 3. The substitution pattern of their most potent compound (24) was similar as 23 with a K i value of 7.5 nM. Modeling of this compound showed that the basic tertiary amine possibly interacts with an aspartic acid in TM VII (Asp302) and the pyridine ring could provide p-p interaction with an aromatic residue in the receptor.…”

Section: Pyrrolo[12-a]pyrimidin-7-one Derivativesmentioning

confidence: 85%

“…22 The chirality and ring size of the alkyl cyclic amine substituent at position 4 was further investigated. 24 It was shown that the S-configuration was generally favored and that ring size was not a critical determinant in binding affinity. Together with the removal of the N-methyl group of this substituent, compound 5 was obtained with an IC 50 -value of 10 nM at the rat GnRH receptor.…”

Section: B Quinolin-2-one Derivativesmentioning

confidence: 99%

“…Together with the removal of the N-methyl group of this substituent, compound 5 was obtained with an IC 50 -value of 10 nM at the rat GnRH receptor. 24 At Merck parallel efforts were undertaken to replace the 6-nitro group by different substituted amide groups. 23,25 In both articles, the pyrimidinecarboxamide was the superior substituent (6).…”

Section: B Quinolin-2-one Derivativesmentioning

confidence: 99%

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G protein‐coupled receptors of the hypothalamic–pituitary–gonadal axis: A case for gnrh, LH, FSH, and GPR54 receptor ligands

Heitman

IJzerman

2008

Medicinal Research Reviews

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The hypothalamic-pituitary-gonadal (HPG) axis, important in reproduction and sex hormone-dependent diseases, is regulated by a number of G protein-coupled receptors. The recently "deorphanized" GPR54 receptor activated by the peptide metastin is thought to be the key regulator of the axis, mainly by releasing gonadotropin-releasing hormone (GnRH) from the hypothalamus. The latter decapeptide, through the activation of the GnRH receptor in the anterior pituitary, causes the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which subsequently activate their respective receptors on the gonadotrope cells. In this review we will discuss the small molecule agonists and antagonists that are currently being developed to intervene with the action of these four receptors. For GnRH receptors, 14 different chemical classes of non-peptidic antagonists have been reported, while for the LH receptor three classes of agonists have been described. Both agonists and antagonists have been introduced for the FSH receptor. Recently, the first non-peptidic agonist for GPR54 was reported.

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Section: Pyrrolo[12-a]pyrimidin-7-one Derivativesmentioning

confidence: 85%

Section: B Quinolin-2-one Derivativesmentioning

confidence: 99%

Section: B Quinolin-2-one Derivativesmentioning

confidence: 99%

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G protein‐coupled receptors of the hypothalamic–pituitary–gonadal axis: A case for gnrh, LH, FSH, and GPR54 receptor ligands

Heitman

IJzerman

2008

Medicinal Research Reviews

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“…The following chemical structures (collectively referenced as "pharmacoperones") were utilized; those of the quinolone class are prefaced by the letter "Q" and those of the indole class by the letters "IN" and were produced by Merck and Company (Ashton et al, 2001a;Ashton et al, 2001b;Ashton et al, 2001c;DeVita et al, 1999a;DeVita et al, 1999b;DeVita et al, 2001;Walsh et al, 2000): Q89, (7-chloro-2-oxo-4-{2-[(2S)-piperidin-2-yl]ethoxy}-N-pyrimidin-4-yl-3-(3,4,5-trimethylphenyl)-1,2-dihydroquinoline-6-carboxamide); Q76, (N-(7-chloro-3-(3,5- -chloro-6-[(6,7-dimethoxy-3,4-…”

Section: Methodsmentioning

confidence: 99%

Refolding of misfolded mutant GPCR: Post-translational pharmacoperone action in vitro

Janovick

Brothers

Cornea

et al. 2007

Molecular and Cellular Endocrinology

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SUMMARYAll reported GnRH receptor mutants (causing human hypogonadotropic hypogonadism) are misfolded proteins that cannot traffic to the plasma membrane. Pharmacoperones correct mis-folding and rescue mutants, routing them to the plasma membrane where they regain function. Because pharmacoperones are often peptidomimetic antagonists, these must be removed for receptor function after rescue; in vivo this necessitates pulsatile pharmacoperone administration. As an antecedent to in vivo studies, we determined whether pharmacoperones need to be present at the time of synthesis or whether previously misfolded proteins could be refolded and rescued. Accordingly, we blocked either protein synthesis or intra-cellular transport. Biochemical and morphological studies using 12 mutants and 10 pharmacoperones representing three different chemical classes show that previously synthesized mutant proteins, retained by the quality control system (QCS), are rescued by pharmacoperones, showing that pharmacoperone administration in vivo likely need not consider whether the target protein is being synthesized at the time of drug administration.

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“…[9] The ester function was next reduced with lithium borohydride in tetrahydrofuran (THF) to give primary alcohol 5 in 82% yield (Scheme 2). [11] We noticed some discrepancies in the literature, such as specific optical rotation values for this known Boc-homoprolinol (5). Despite it being well accepted that Arndt-Eistert synthesis leads to complete retention of stereochemistry, [10,12] partial erosion of stereochemical purity could in principle have occurred prior to the Wolff rearrangement step, and a rigorous investigation of the enantiofidelity up to this point was accordingly undertaken.…”

mentioning

confidence: 97%

Efficient Arndt–Eistert Synthesis of Selective 5-HT₇ Receptor Antagonist SB-269970

Schjøth-Eskesen

2009

Synthetic Communications

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Investigation of the 4-O-alkylamine substituent of non-peptide quinolone GnRH receptor antagonists

Cited by 51 publications

References 9 publications

G protein‐coupled receptors of the hypothalamic–pituitary–gonadal axis: A case for gnrh, LH, FSH, and GPR54 receptor ligands

G protein‐coupled receptors of the hypothalamic–pituitary–gonadal axis: A case for gnrh, LH, FSH, and GPR54 receptor ligands

Refolding of misfolded mutant GPCR: Post-translational pharmacoperone action in vitro

Efficient Arndt–Eistert Synthesis of Selective 5-HT₇ Receptor Antagonist SB-269970

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Investigation of the 4-O-alkylamine substituent of non-peptide quinolone GnRH receptor antagonists

Cited by 51 publications

References 9 publications

G protein‐coupled receptors of the hypothalamic–pituitary–gonadal axis: A case for gnrh, LH, FSH, and GPR54 receptor ligands

G protein‐coupled receptors of the hypothalamic–pituitary–gonadal axis: A case for gnrh, LH, FSH, and GPR54 receptor ligands

Refolding of misfolded mutant GPCR: Post-translational pharmacoperone action in vitro

Efficient Arndt–Eistert Synthesis of Selective 5-HT7 Receptor Antagonist SB-269970

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Efficient Arndt–Eistert Synthesis of Selective 5-HT₇ Receptor Antagonist SB-269970