ANIMAL EXPERIMENT;
AREA UNDER THE CURVE;
ARTICLE;
BIOLOGICAL ACTIVITY;
BIOLUMINESCENCE;
COLUMN CHROMATOGRAPHY;
CONTROLLED STUDY;
DRUG BIOAVAILABILITY;
DRUG CLEARANCE;
DRUG EFFICACY;
DRUG HALF LIFE;
DRUG SAFETY;
DRUG SOLUBILITY;
DRUG STRUCTURE;
DRUG SYNTHESIS;
HIGH THROUGHPUT SCREENING;
HUMAN;
HUMAN CELL;
HYDROGEN BOND;
LIPOPHILICITY;
LUTEINIZING HORMONE BLOOD LEVEL;
MACACA FASCICULARIS;
MALE;
NONHUMAN;
PHARMACODYNAMICS;
RACEMIZATION;
RAT;
RECEPTOR BINDING;
STRUCTURE ACTIVITY RELATION;
VOLUME OF DISTRIBUTION;
X RAY CRYSTALLOGRAPHY;
ANIMAL;
ANTAGONISTS AND INHIBITORS;
BLOOD;
BRAIN;
CACO 2 CELL LINE;
CHEMISTRY;
CHO CELL LINE;
CRICETULUS;
DRUG DEVELOPMENT;
DRUG EFFECTS;
ENDOCRINE SYSTEM DISEASES;
GENETICS;
METABOLISM;
PROCEDURES;
SPRAGUE DAWLEY RAT;
SYNTHESIS;
NK3 receptor antagonists: The next generation of antipsychotics?
and references cited therein
Spooren, W.; Riemer, C.; Meltzer, H. NK3 receptor antagonists: the next generation of antipsychotics? Nature Rev. Drug Discovery 2005, 4, 967 - 975 and references cited therein
Progress in the development of neurokinin 3 modulators for the treatment of schizophrenia: Molecule development and clinical progress
and references therein
Dawson, L. A.; Porter, R. A. Progress in the development of neurokinin 3 modulators for the treatment of schizophrenia: molecule development and clinical progress Future Med. Chem. 2013, 5, 1525 - 1546 and references therein
The kisspeptin-GnRH pathway in human reproductive health and disease
Skorupskaite, K.; George, J. T.; Anderson, R. A. The kisspeptin-GnRH pathway in human reproductive health and disease Hum. Reprod. Update 2014, 0, 1 - 16
Neurokinin B and the hypothalamic regulation of reproduction
Rance, N. E.; Krajewski, S. J.; Smith, M. A.; Cholanian, M.; Dacks, P. A. Neurokinin B and the hypothalamic regulation of reproduction Brain Res. 2010, 1364, 116 - 128
Note that KNDy neurons are devoid of GPR54 (or Kiss 1-R), which is mainly expressed on the GnRH neurons located in the medial preoptic area (mPOA) in hypothalamus projecting into the median eminence (ME). These observations are anatomically consistent with the downstream role of GPR54/kisspeptin vis-à-vis NKB/NK3R (Figure 2).
9
84927599841
note
In this context, the colocalization within KNDy neurons of estrogen receptor alpha (ERα, or GPR30) and progesterone receptor (PR) is noteworthy based on its role in the HPG feedback loop (Figure 2), a subject that is under active investigation in this field5.
10
84927668619
note
Structure 3 is the "compound 27 " (drawn incorrectly in racemic form) in the reference cited under footnote 3.
11
84927606172
Preparation of [1,2,4]triazolo[4,3-a ]pyrazine compounds as selective NK-3 receptor antagonists, pharmaceutical compositions containing same, and their methods of use
PCT International Application , October 6
Hoveyda, H.; Roy, M.-O.; Fraser, G.; Dutheuil, G. Preparation of [1,2,4]triazolo[4,3-a ]pyrazine compounds as selective NK-3 receptor antagonists, pharmaceutical compositions containing same, and their methods of use. PCT International Application WO121137-A1, October 6, 2011.
Preparation of novel chiral 7-acyl-8-substituted-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a ]pyrazines as selective NK-3 receptor antagonists, pharmaceutical composition, methods for use in NK-3 receptor mediated disorders and chiral synthesis thereof
PCT International Application , April 11
Hoveyda, H.; Dutheuil, G.; Fraser, G.; Roy, M.-O.; El Bousmaqui, M.; Batt, F. Preparation of novel chiral 7-acyl-8-substituted-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a ]pyrazines as selective NK-3 receptor antagonists, pharmaceutical composition, methods for use in NK-3 receptor mediated disorders and chiral synthesis thereof. PCT International Application WO050424-A1, April 11, 2013.
TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for Neurokinin B in the central control of reproduction
Note: TAC3 = NKB and TACR3 = NK3R
Topaloglu, A. K.; Reimann, F.; Guclu, M.; Guclu, M.; Yalin, A. S.; Kotan, L. D.; Porter, K. M.; Serin, A.; Mungan, N. O.; Cook, J. R.; Ozbek, M. N.; Imamoglu, S.; Akalin, N. S.; Yuksel, B.; O'Rahilly, S.; Semple, R. K. TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for Neurokinin B in the central control of reproduction Nature Genet. 2009, 41, 354 - 358 Note: TAC3 = NKB and TACR3 = NK3R;
Uncovering novel reproductive defects in neurokinin B receptor null mice: Closing the gap between mice and men
Yang, J. J.; Caligioni, C. S.; Chan, Y.-M.; Seminara, S. B. Uncovering novel reproductive defects in neurokinin B receptor null mice: closing the gap between mice and men Endocrinology 2012, 153, 1498 - 1508
Progesterone action in endometrial cancer, endometriosis, uterine fibroids and breast cancer
Kim, J. J.; Kurita, T.; Bulun, S. E. Progesterone action in endometrial cancer, endometriosis, uterine fibroids and breast cancer Endocr. Rev. 2013, 34, 1 - 33
Drug Insight: Clinical use of agonists and antagonists of luteinizing-hormone-releasing hormone (LHRH)
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Engel, J. B.; Schally, A. V. Drug Insight: clinical use of agonists and antagonists of luteinizing-hormone-releasing hormone (LHRH) Nature Clin. Pract. 2007, 3, 157 - 167 and references therein.
Long-term use of gonadotropin-releasing hormone analogs and hormone replacement therapy in the management of endometriosis: A randomized trial with a 6-year follow-up
Pierce, S. J.; Gazvani, M. R.; Farquharson, R. G. Long-term use of gonadotropin-releasing hormone analogs and hormone replacement therapy in the management of endometriosis: a randomized trial with a 6-year follow-up Fertil. Steril. 2000, 74, 964 - 968
Integrated pharmacometrics and systems pharmacology model-based analyses to guide GnRH receptor modulator development for management of endometriosis
Riggs, M. M.; Bennetts, M.; van der Graaf, P. H.; Martin, S. W. Integrated pharmacometrics and systems pharmacology model-based analyses to guide GnRH receptor modulator development for management of endometriosis Pharmacometrics Syst. Pharmacol. 2012, 1, e11
GnRH pulse frequency-dependent differential regulation of LH and FSH gene expression
Thompson, I. R.; Kaiser, U. B. GnRH pulse frequency-dependent differential regulation of LH and FSH gene expression Mol. Cell. Endocrinol. 2014, 385, 28 - 35
Neuroendocrine dysfunction in polycystic ovary syndrome
Solozarno, C. M.; Beller, J. P.; Abshire, M. Y.; Collins, J. S.; McCartney, C. R.; Marshall, J. C. Neuroendocrine dysfunction in polycystic ovary syndrome Steroids 2012, 77, 332 - 337
The origins and sequelae of abnormal neuroendocrine function in polycystic ovary syndrome
Blank, S. K.; McCartney, C. R.; Marshall, J. C. The origins and sequelae of abnormal neuroendocrine function in polycystic ovary syndrome Hum. Reprod. Update 2006, 4, 351 - 361
SR142801, the first potent non-peptide antagonist of the tachykinin NK3 receptor
Emonds-Alt, X.; Bichon, D.; Ducoux, J. P.; Heaulme, M.; Miloux, B.; Poncelet, M.; Proietto, V.; Van Broeck, D.; Vilain, P.; Neliat, G.; Soubrié, P.; Le Fur, G.; Brelère, J. C. SR142801, the first potent non-peptide antagonist of the tachykinin NK3 receptor Life Sci. 1995, 56, PL27 - PL32
Nonpeptide tachykinin receptor antagonists: I. Pharmacological and pharmacokinetic characterization of SB223412, a novel, potent and selective neurokinin-3 receptor antagonist
Sarau, H. M.; Griswold, D. E.; Potts, W.; Foley, J. J.; Schmidt, D. B.; Webb, E. F.; Martin, L. D.; Brawner, M. E.; Elshourbagy, N. A.; Medhurst, A. D.; Giardina, G. M.; Hay, D. W. P. Nonpeptide tachykinin receptor antagonists: I. Pharmacological and pharmacokinetic characterization of SB223412, a novel, potent and selective neurokinin-3 receptor antagonist J. Pharmacol. Exp. Ther. 1997, 281, 1303 - 1311
The selective neurokinin 3 antagonist AZD2624 does not improve symptoms or cognition in schizophrenia: A proof-of-principle study
Litman, R. E.; Smith, M. A.; Desai, D. G.; Simpson, T.; Sweitzer, D.; Kanes, S. J. The selective neurokinin 3 antagonist AZD2624 does not improve symptoms or cognition in schizophrenia: A proof-of-principle study J. Clin. Psychopharmacol. 2014, 34, 199 - 204
NK3 receptor antagonist compound for use in a method for the treatment of polycystic ovary syndrome
PCT International Application, October 23
Gilmour, P. S.; Tony, H. O.; Rahul, K.; Webber, L. NK3 receptor antagonist compound for use in a method for the treatment of polycystic ovary syndrome. PCT International Application WO170648-A1, October 23, 2014.
Discovery of 3-aryl-5-acylpiperazinyl-pyrazoles as antagonists to the NK3 receptor
Hoveyda, H. R.; Roy, M.-O.; Blanc, S.; Noël, S.; Salvino, J. M.; Ator, M. A.; Fraser, G. Discovery of 3-aryl-5-acylpiperazinyl-pyrazoles as antagonists to the NK3 receptor Bioorg. Med. Chem. Lett. 2011, 21, 1991 - 1996
Adaptation of aequorin functional assay to high throughput screening
Le Poul, E.; Hisada, S.; Mizuguchi, Y.; Dupriez, V. J.; Burgeon, E.; Detheux, M. Adaptation of aequorin functional assay to high throughput screening J. Biomol. Screening 2002, 7, 57 - 65
1H NMR spectroscopic data for 4 clearly suggested presence of prototropic tautomerism. See Supporting Information for further details.
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Molecular field extrema as descriptors of biological activity: Definition and validation
Cheesright, T.; Mackey, M.; Rose, S.; Vinter, A. Molecular field extrema as descriptors of biological activity: definition and validation J. Chem. Inf. Model. 2006, 46, 665 - 676
Discovery and optimization of novel antagonists to the human neurokinin-3 receptor for the treatment of sex-hormone disorders (Part II)
to be submitted for publication
Hoveyda, H. R.; Fraser, G. L.; Dutheuil, G.; El Bousmaqui, M.; Korac, J.; Lenoir, F.; Lapin, A.; Noël, S. Discovery and optimization of novel antagonists to the human neurokinin-3 receptor for the treatment of sex-hormone disorders (Part II). ACS Med. Chem. Lett., to be submitted for publication.
A rapid and efficient synthesis of imidazo [1,2- a ] and 1,2,4-triazolo[4,3- a ]-piperazine carboxylic acids
McCort, G. A.; Pascal, J. C. A rapid and efficient synthesis of imidazo [1,2- a ] and 1,2,4-triazolo[4,3- a ]-piperazine carboxylic acids Tetrahedron Lett. 1992, 33, 4443 - 4446
Intramolecular Friedel-Crafts-type reactions involving N -acyliminium ions derived from glycine templates
Sánchez, J. D.; Ramos, M. T.; Avendano, C. Intramolecular Friedel-Crafts-type reactions involving N -acyliminium ions derived from glycine templates J. Org. Chem. 2001, 66, 5731 - 5735
Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings
Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings Adv. Drug Delivery Rev. 1997, 23, 3 - 25
Physicochemical drug properties associated with in vivo toxicological outcomes
Hughes, J. D.; Blagg, J.; Price, D. A.; Bailey, S.; DeCrescenzo, G. A.; Devraj, R. V.; Ellsworth, E.; Fobian, Y. M.; Gibbs, M. E.; Gilles, R. W.; Greene, N.; Huang, E.; Krieger-Burke, T.; Loesel, J.; Wager, T.; Whiteley, L.; Zhang, Y. Physicochemical drug properties associated with in vivo toxicological outcomes Bioorg. Med. Chem. Lett. 2008, 18, 4872 - 4875
Improving the odds of success in drug discovery: Choosing the best compounds for in vivo toxicology studies
Wager, T.; Kormos, B. L.; Brady, J. T.; Will, Y.; Aleo, M. D.; Stedman, D. B.; Kuhn, M.; Chandrasekaran, R. Y. Improving the odds of success in drug discovery: choosing the best compounds for in vivo toxicology studies J. Med. Chem. 2013, 56, 9771 - 9779
Reducing the risk of drug attrition associated with physicochemical properties
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Leeson, P. D.; Empfield, J. R. Reducing the risk of drug attrition associated with physicochemical properties Annu. Rep. Med. Chem. 2010, 45, 381 - 391 and references therein.
Probing the links between in vitro potency, ADMET and physicochemical parameters
Gleeson, M. P.; Hersey, A.; Montanari, D.; Overington, J. Probing the links between in vitro potency, ADMET and physicochemical parameters Nature Rev. Drug Discovery 2011, 11, 197 - 208
The influence of drug-like concepts in decision-making in medicinal chemistry
Leeson, P. D.; Springthorpe, B. The influence of drug-like concepts in decision-making in medicinal chemistry Nature Rev. Drug Discovery 2007, 6, 881 - 890
The role of ligand efficiency metrics in drug discovery
Hopkins, A. L.; Keserü, G. M.; Lesson, P. D.; Rees, D. C.; Reynolds, C. H. The role of ligand efficiency metrics in drug discovery Nature Rev. Drug Discovery 2014, 13, 105 - 121
Escape from flatland: Increasing saturation as an approach to improving clinical success
Lovering, F.; Bikker, J.; Humblet, C. Escape from flatland: increasing saturation as an approach to improving clinical success J. Med. Chem. 2009, 52, 6752 - 6756
The impact of aromatic ring count on compound developability - Are too many aromatic rings a liability in drug design?
Ritchie, T. J.; Macdonald, S. J. F. The impact of aromatic ring count on compound developability-are too many aromatic rings a liability in drug design? Drug Discovery Today 2009, 14, 1011 - 1019
Strategies to improve in vivo toxicology outcomes for basic candidate drug molecules
Luker, T.; Alcaraz, L.; Chohan, K. K.; Blomberg, N.; Brown, D. S.; Butlin, R. J.; Elebring, T.; Griffin, A. M.; Guile, S.; St-Gallay, S.; Swahn, B.-M.; Swallow, S.; Waring, M. J.; Wenlock, M. C.; Leeson, P. D. Strategies to improve in vivo toxicology outcomes for basic candidate drug molecules Bioorg. Med. Chem. Lett. 2011, 21, 5673 - 5679
Getting physical in drug discovery: A contemporary perspective on solubility and hydrophobicity
Hill, A. P.; Young, R. J. Getting physical in drug discovery: a contemporary perspective on solubility and hydrophobicity Drug Discovery Today 2010, 15, 648 - 655
Rognan D. Ed.; Wiley-VCH: Darmstadt, Germany, and references therein
Klabunde, T. Chemogenomics approaches to ligand design. In Ligand Design for G Protein-Coupled Receptors; Rognan, D., Ed.; Wiley-VCH: Darmstadt, Germany, 2006; pp 115 - 135 and references therein.
ΔLLE values throughout this report are calculated using log D 7.4-derived LLE values, except when noted as ΔLLEclogP, indicating that clogP-derived LLE values were used.
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The methylation effect in medicinal chemistry
Barreiro, E. J.; Kümmerle, A. E.; Fraga, C. A. The methylation effect in medicinal chemistry Chem. Rev. 2011, 111, 5215 - 5246
Jamieson, C.; Moir, E. M.; Rankovic, Z.; Wishart, G. Strategies and tactics for hERG optimization. In Antitargets; Vaz, R. J.; Klabunde, T., Eds.; Wiley-VCH: Darmstadt, Germany, 2008; pp 423 - 456.
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CommonOrganicChemstry.com resources web page http://www.commonorganicchemistry.com/Sidebar/Resources.htm (accessed February 24, 2015).
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Hydrogen-bond acceptor and donor properties of divalent sulfur (Y-S-Z and R-S-H)
Allen, F. H.; Bird, C. M.; Rowland, R. S.; Raithby, P. R. Hydrogen-bond acceptor and donor properties of divalent sulfur (Y-S-Z and R-S-H) Acta Crystallogr., Sect. B: Struct. Sci. 1997, B53, 696 - 701
Tachykinins and tachykinin receptors: Structure and activity relationships
Almeida, T. A.; Rojo, J.; Nieto, P. M.; Hernandez, M.; Martin, J. D.; Candenas, M. L. Tachykinins and tachykinin receptors: structure and activity relationships Curr. Med. Chem. 2004, 11, 2045 - 2081
Of the two gold standards, osanetant (1a) displayed a particularly poor off-target selectivity profile. For instance, even at 1 μM it displayed ≥ 50% inhibition vs muscarinic (M3, M4 and M5), dopamine D3, opioid (δ, κ and μ), serotonin (5HT1A, 2A, 2B and 5HT7 subtypes), histamine H2, as well as on norepinephrine and dopamine transporters. Talnetant (2a) showed ≥60% inhibition against adenosine (A1, A3), benzodiazepine, CCK2 and prostanoid (EP4).
67
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Elsevier: Burlington, MA
Kerns, E. H.; Di, L. Drug-Like Properties: Concepts, Structure Design and Methods: from ADME to Toxicity Optimization; Elsevier: Burlington, MA, 2008; p 233.
Apparent absolute oral bioavailability in excess of 100% for a vitronectin receptor antagonist (SB-265123) in rat. II. Studies implicating transporter-mediated intestinal secretion
Ward, K. M.; Hardy, L. B.; Kehler, J. R.; Azzarano, L. M.; Smith, B. R. Apparent absolute oral bioavailability in excess of 100% for a vitronectin receptor antagonist (SB-265123) in rat. II. Studies implicating transporter-mediated intestinal secretion Xenobiotica 2004, 34, 367 - 377
The disposition of voriconazole in mouse, rat, rabbit, guinea pig, dog and human
Roffey, S. J.; Cole, S.; Comby, P.; Gibson, D.; Jezequel, S. G.; Nedderman, A. N. R.; Smith, D. A.; Walker, D. K.; Wood, N. The disposition of voriconazole in mouse, rat, rabbit, guinea pig, dog and human Drug Metab. Dispos. 2003, 31, 731 - 741
VN/14-1 induces ER stress and autophagy in HP-LTLC human breast cancer cells and has excellent oral pharmacokinetic profile in female Sprague-Dawley rats
and references therein
Godbole, A. M.; Ramalingam, S.; Ramamurthy, V. P.; Khandelwal, A.; Bruno, R. D.; Upreti, V. V.; Gediya, L. K.; Purushottamachar, P.; Mbatia, H. W.; Addya, S.; Ambulos, N.; Njar, V. C. O. VN/14-1 induces ER stress and autophagy in HP-LTLC human breast cancer cells and has excellent oral pharmacokinetic profile in female Sprague-Dawley rats Eur. J. Pharmacol. 2014, 734, 98 - 104 and references therein
Wolf, M. E., Ed. Prinicples and Practice John Wiley & Sons: New York
Benet, L.Z.; Perotti, B. Y. T. Drug absorption, distribution and elimination. In Burger's Medicinal Chemistry and Durg Discovery, Vol. 1: Prinicples and Practice; Wolf, M. E., Ed.; John Wiley & Sons: New York, 1995; p 122.
Kerns, E. H.; Di, L. Drug-Like Properties: Concepts, Structure Design and Methods: From ADME to Toxicity Optimization; Elsevier: Burlington, MA, 2008; pp 122 - 135 and references therein.
Predicting plasma protein binding of drugs: A new approach
Kratochwil, N. A.; Huber, W.; Muller, F.; Kansy, M.; Gerber, P. R. Predicting plasma protein binding of drugs: a new approach Biochem. Pharmacol. 2002, 64, 1355 - 1374
Although compartmental equilibrium (including influences of transporters) has not been formally established herein, given the good agreement between (B/P)u values at 10 min and 1 h time points, the measured values likely reflect a state of equilibrium.
79
84927615938
note
In case of talnetant (2a), the (B/P)u > 1 reflects its 33-fold higher bfu (0.01) against fu (0.0003). With compd 3, due to its poor solubility, DMA/PEG-400 formulation had to be used (as footnoted in Table 6) that may impact the values discussed herein.
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NK3 Receptor Signaling Maintains LH Pulse Secretion, Mean Plasma LH Levels and Induces Testicular Testosterone Release; Studies in Cynomolgus Monkey (Macaca Fascicularis) and Corriedale Ewe
Presented at SAT-146
Fraser, G. L.; Hoveyda, H. R.; Roy, M.-O.; Ramaswamy, S.; Plant, T. M.; Smith, J.; Clarke, I. NK3 receptor signaling maintains LH pulse secretion, mean plasma LH levels and induces testicular testosterone release; studies in cynomolgus monkey (Macaca fascicularis) and Corriedale ewe. Presented at ENDO Meeting, San Francisco, CA, 2013, SAT-146.
Accessibility of low-molecular-mass molecules to the median eminence and arcuate hypothalamic nucleus of adult mouse
Morita, S.; Miyata, S. Accessibility of low-molecular-mass molecules to the median eminence and arcuate hypothalamic nucleus of adult mouse Cell Biochem. Funct. 2013, 3, 668 - 677
The NK3 receptor antagonist ESN364 slows pulsatile LH secretion and moderates levels of ovarian hormones throughout the menstrual cycle
to be submitted for publication
Fraser, G. L.; Hoveyda, H. R.; Rao, A.; Clarke, I. J.; Ramaswamy, S.; Plant, T. M.; Rose, C.; Millar, R. P. The NK3 receptor antagonist ESN364 slows pulsatile LH secretion and moderates levels of ovarian hormones throughout the menstrual cycle. Endocrinology, to be submitted for publication.
Discovery and development of ESN364, a novel NK3 antagonist for the treatment of hormone-dependent pathologies
Presented at
Fraser, G. L. Discovery and development of ESN364, a novel NK3 antagonist for the treatment of hormone-dependent pathologies. Presented at ENDO Meeting, Chicago, IL, 2014, S44-2.
