Identification and initial structure-activity relationships of a novel non-peptide quinolone GnRH receptor antagonist

DeVita, Robert J.; Hollings, Darius D.; 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)00446-1

Cited by 54 publications

(25 citation statements)

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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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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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“…22 The lead compound (3), which had micromolar affinity for the rat GnRH receptor (IC 50 ¼ 10 mM), was identified by screening an in-house compound library. At first the 2-pyridyl substituent at position 4 was replaced by other (nitrogen-containing) ring systems.…”

Section: B Quinolin-2-one Derivativesmentioning

confidence: 99%

“…A 10-fold increase in potency was obtained when a 6-nitro group was incorporated resulting in the first nanomolar-affinity compound of this class (4; IC 50 ¼ 32 nM). 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.…”

Section: B Quinolin-2-one Derivativesmentioning

confidence: 99%

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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“…16 During the synthesis of compound (±)-8, rearrangement through a ring opening (quarternization) reaction was observed (Scheme 2) under basic conditions. 17 Two nitroindole derivatives, (±)-4 and the rearranged product 9 were easily separated by silica gel column chromatography. Following the same synthetic protocol and coupling to the thiophene-2-carbimidothioate 5 or the furan-2-carbimidothioate 10 as outlined in Scheme 2 provided the target compounds 11 and 12, respectively.…”

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confidence: 99%

1,5-Disubstituted indole derivatives as selective human neuronal nitric oxide synthase inhibitors

Renton¹,

Speed²,

Maddaford³

et al. 2011

Bioorganic & Medicinal Chemistry Letters

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A series of 1,6-disubstituted indole derivatives was designed, synthesized and evaluated as inhibitors of human nitric oxide synthase (NOS). By varying the basic amine side chain at the 1-position of the indole ring, several potent and selective inhibitors of human neuronal NOS were identified. In general compounds with bulkier side chains displayed increased selectivity for nNOS over eNOS and iNOS isoforms. One of the compounds, (R)-8 was shown to reduce tactile hyperesthesia (allodynia) after oral administration (30 mg/kg) in an in vivo rat model of dural inflammation relevant to migraine pain. Keywords1,6-Disubstitued indole derivatives; Nitric oxide; Nitric oxide synthase; Nitric oxide synthase inhibitors; Selective neuronal nitric oxide synthase inhibitors Nitric oxide (NO) is an inorganic free radical that has diverse roles both in normal and pathological processes, including the regulation of blood pressure, neurotransmission and macrophage defense systems. 1 NO is synthesized from the enzyme catalysis of L-arginine to L-citrulline by three isoforms of nitric oxide synthase (NOS): two constitutive forms in neuronal cells (nNOS) and endothelial cells (eNOS), and an inducible form in macrophage cells (iNOS). Overstimulation or overproduction of NO by nNOS and iNOS has been shown to play a key role in several disorders, including septic shock, arthritis, diabetes, ischemiareperfusion injury, pain and various neurodegenerative diseases. 2 However, any inhibitors to treat these conditions must avoid eNOS inhibition as this will lead to unwanted effects such as enhanced white cell and platelet activation, hypertension and atherogenesis. 3 Therefore, the development of selective NOS inhibitors is of considerable interest, both from a therapeutic perspective and also as specific pharmacological tools. 4 Although there is low homology among the three NOS primary sequences (~50%), the active sites of the enzymes appears to be relatively conserved with 16 out of 18 residues within 6 Å being identical, presumably explains the difficulty obtaining selective NOS The pharmacophore model we adopted for the arginine binding site of the NOS enzyme includes a guanidine isosteric group (amidine group) and a basic amine group, both attached to a central aryl scaffold (indole core) as shown in Figure 1. 4,15 The amidine group makes an important bidentate interaction with the conserved glutamic acid residue to achieve the necessary potency; whereas the basic amine is assumed to provide the nNOS isoform selectivity. 15 Our design strategy is based on an indole core as an aryl scaffold and exploring various basic amine side chains for achieving the NOS isoform selectivity. As part of our ongoing efforts to find small molecule selective nNOS inhibitors for treating CNS disorders, herein we report the synthesis and biological activity evaluations of a series of 1,6-disubstituted indole derivatives and in vivo activity of (R)-8 in a rat model relevant to migraine pain. 15 Two general approaches were undertaken for the prepa...

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Identification and initial structure-activity relationships of a novel non-peptide quinolone GnRH receptor antagonist

Cited by 54 publications

References 14 publications

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

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

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

1,5-Disubstituted indole derivatives as selective human neuronal nitric oxide synthase inhibitors

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