C Chen

Summary

Affiliation: Neurocrine Biosciences
Country: USA

Publications

  1. ncbi Design, synthesis and structure-activity relationships of novel imidazolo[1,2-a]pyrimid-5-ones as potent GnRH receptor antagonists
    Timothy D Gross
    Department of Medicinal Chemistry, Neurocrine Biosciences, Inc, 10555 Science Center Drive, San Diego, CA 92121, USA
    Bioorg Med Chem Lett 12:2185-7. 2002
  2. ncbi Design and structure-activity relationships of 2-alkyl-3-aminomethyl-6-(3-methoxyphenyl)-7-methyl-8-(2-fluorobenzyl)imidazolo[1,2-a]pyrimid-5-ones as potent GnRH receptor antagonists
    Yun Fei Zhu
    Department of Medicinal Chemistry, Neurocrine Biosciences, Inc, 10555 Science Center Drive, San Diego, California 92121, USA
    J Med Chem 46:1769-72. 2003
  3. ncbi Body weight regulation by selective MC4 receptor agonists and antagonists
    Alam C Foster
    Neurocrine Biosciences Inc, San Diego, California 92121, USA
    Ann N Y Acad Sci 994:103-10. 2003
  4. ncbi MC4 receptor antagonists: a potential treatment for cachexia
    Alan C Foster
    Neurocrine Biosciences Inc, 12790 El Camino Real, San Diego, CA 92130, USA
    IDrugs 8:314-9. 2005
  5. ncbi Arylpropionylpiperazines as antagonists of the human melanocortin-4 receptor
    Wanlong Jiang
    Department of Medicinal Chemistry, Neurocrine Biosciences, Inc, San Diego, CA 92130, USA
    Bioorg Med Chem Lett 16:4674-8. 2006
  6. ncbi Phenylguanidines as selective nonpeptide melanocortin-5 receptor antagonists
    Chen Chen
    Department of Medicinal Chemistry, Neurocrine Biosciences, Inc, 10555 Science Center Drive, San Diego, California 92121, USA
    J Med Chem 47:4083-8. 2004
  7. ncbi Discovery of 1-[2-[(1S)-(3-dimethylaminopropionyl)amino-2-methylpropyl]-4-methylphenyl]-4-[(2R)-methyl-3-(4-chlorophenyl)-propionyl]piperazine as an orally active antagonist of the melanocortin-4 receptor for the potential treatment of cachexia
    Chen Chen
    Department of Medicinal Chemistry, Neurocrine Biosciences, Inc, 12790 El Camino Real, San Diego, California 92130, USA
    J Med Chem 50:5249-52. 2007
  8. doi Potent and orally bioavailable zwitterion GnRH antagonists with low CYP3A4 inhibitory activity
    Chen Chen
    Department of Medicinal Chemistry, Neurocrine Biosciences, Inc, 12790 El Camino Real, San Diego, CA 92130, USA
    Bioorg Med Chem Lett 18:3301-5. 2008
  9. doi Pharmacological and pharmacokinetic characterization of 2-piperazine-alpha-isopropyl benzylamine derivatives as melanocortin-4 receptor antagonists
    Chen Chen
    Department of Medicinal Chemistry, Neurocrine Biosciences, Inc, 12790 El Camino Real, San Diego, CA 92130, USA
    Bioorg Med Chem 16:5606-18. 2008
  10. doi Discovery of sodium R-(+)-4-{2-[5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyrate (elagolix), a potent and orally available nonpeptide antagonist of the human
    Chen Chen
    Department of Medicinal Chemistry, Neurocrine Biosciences, Inc, 12790 El Camino Real, San Diego, California 92130, USA
    J Med Chem 51:7478-85. 2008

Collaborators

Detail Information

Publications71

  1. ncbi Design, synthesis and structure-activity relationships of novel imidazolo[1,2-a]pyrimid-5-ones as potent GnRH receptor antagonists
    Timothy D Gross
    Department of Medicinal Chemistry, Neurocrine Biosciences, Inc, 10555 Science Center Drive, San Diego, CA 92121, USA
    Bioorg Med Chem Lett 12:2185-7. 2002
    ..6 nM, compared with 2b, K(i)=230 nM) in which the 7-position of the imidazolo[1,2-a]pyrimidone core was substituted with a methyl group, and the ester at the 6-position was replaced by the 3-methoxyphenyl group...
  2. ncbi Design and structure-activity relationships of 2-alkyl-3-aminomethyl-6-(3-methoxyphenyl)-7-methyl-8-(2-fluorobenzyl)imidazolo[1,2-a]pyrimid-5-ones as potent GnRH receptor antagonists
    Yun Fei Zhu
    Department of Medicinal Chemistry, Neurocrine Biosciences, Inc, 10555 Science Center Drive, San Diego, California 92121, USA
    J Med Chem 46:1769-72. 2003
    ..We report here the use of a 2-alkyl group on the imidazolo[1,2-a]pyrimidone core to generate potent GnRH receptor antagonists. This discovery enabled us to obtain smaller but equally potent GnRH receptor antagonists...
  3. ncbi Body weight regulation by selective MC4 receptor agonists and antagonists
    Alam C Foster
    Neurocrine Biosciences Inc, San Diego, California 92121, USA
    Ann N Y Acad Sci 994:103-10. 2003
    ..The current progress with receptor-selective small molecule agonist and antagonist drugs should enable the therapeutic potential of MC4 receptor activation and inhibition to be assessed in the clinic in the near future...
  4. ncbi MC4 receptor antagonists: a potential treatment for cachexia
    Alan C Foster
    Neurocrine Biosciences Inc, 12790 El Camino Real, San Diego, CA 92130, USA
    IDrugs 8:314-9. 2005
    ..MC4 antagonists are an attractive therapeutic approach for cachexia that may ameliorate the loss of lean body mass in cachectic patients...
  5. ncbi Arylpropionylpiperazines as antagonists of the human melanocortin-4 receptor
    Wanlong Jiang
    Department of Medicinal Chemistry, Neurocrine Biosciences, Inc, San Diego, CA 92130, USA
    Bioorg Med Chem Lett 16:4674-8. 2006
    ..Further potency enhancement was observed when a glycine or beta-alanine was incorporated onto the benzylamine. Some compounds demonstrated good potency, moderate selectivity, and oral bioavailability...
  6. ncbi Phenylguanidines as selective nonpeptide melanocortin-5 receptor antagonists
    Chen Chen
    Department of Medicinal Chemistry, Neurocrine Biosciences, Inc, 10555 Science Center Drive, San Diego, California 92121, USA
    J Med Chem 47:4083-8. 2004
    ..Compound 10 had a K(i) value of 2.1 nM in the binding assay and an IC(50) of 72 nM in the functional assay. Some analogues such as 13 from this series possessed weak agonist activity at the human MC4 receptor...
  7. ncbi Discovery of 1-[2-[(1S)-(3-dimethylaminopropionyl)amino-2-methylpropyl]-4-methylphenyl]-4-[(2R)-methyl-3-(4-chlorophenyl)-propionyl]piperazine as an orally active antagonist of the melanocortin-4 receptor for the potential treatment of cachexia
    Chen Chen
    Department of Medicinal Chemistry, Neurocrine Biosciences, Inc, 12790 El Camino Real, San Diego, California 92130, USA
    J Med Chem 50:5249-52. 2007
    ..This compound possessed high water solubility and exhibited good metabolic profiles. In animals, 10d showed moderate to good oral bioavailability and promoted food intake in tumor-bearing mice after oral administration...
  8. doi Potent and orally bioavailable zwitterion GnRH antagonists with low CYP3A4 inhibitory activity
    Chen Chen
    Department of Medicinal Chemistry, Neurocrine Biosciences, Inc, 12790 El Camino Real, San Diego, CA 92130, USA
    Bioorg Med Chem Lett 18:3301-5. 2008
    ..Highly potent hGnRH antagonists with low CYP3A4 inhibitory liability, such as 8a and 8d, were identified. Thus, 8a had a K(i) of 2.2 nM at GnRH-R and an IC(50) of 36 microM at CYP3A4...
  9. doi Pharmacological and pharmacokinetic characterization of 2-piperazine-alpha-isopropyl benzylamine derivatives as melanocortin-4 receptor antagonists
    Chen Chen
    Department of Medicinal Chemistry, Neurocrine Biosciences, Inc, 12790 El Camino Real, San Diego, CA 92130, USA
    Bioorg Med Chem 16:5606-18. 2008
    ..Similar in vivo effects were also observed when 11d was dosed orally at 20mg/kg. These results provide further evidence that a potent and selective MC4R antagonist has potential in the treatment of cancer cachexia...
  10. doi Discovery of sodium R-(+)-4-{2-[5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyrate (elagolix), a potent and orally available nonpeptide antagonist of the human
    Chen Chen
    Department of Medicinal Chemistry, Neurocrine Biosciences, Inc, 12790 El Camino Real, San Diego, California 92130, USA
    J Med Chem 51:7478-85. 2008
    ..Oral administration of 10b suppressed luteinizing hormone in castrated macaques. These efforts led to the identification of 10b as a clinical compound for the treatment of endometriosis...
  11. ncbi Optimization of 3-phenylpyrazolo[1,5-a]pyrimidines as potent corticotropin-releasing factor-1 antagonists with adequate lipophilicity and water solubility
    Chen Chen
    Department of Medicinal Chemistry, Neurocrine Biosciences, Inc, 10555 Science Center Drive, San Diego, CA 92121, USA
    Bioorg Med Chem Lett 14:3669-73. 2004
    ..Moreover, this compound had proper lipophilicity (log D = 2.78) and good solubility in water (>10mg/mL), and exhibited good plasma and brain exposure when given orally...
  12. ncbi Recent advances in small molecule antagonists of the corticotropin-releasing factor type-1 receptor-focus on pharmacology and pharmacokinetics
    C Chen
    Department of Medicinal Chemistry, Neurocrine Biosciences Inc, 12790 El Camino Real, San Diego, CA 92130, USA
    Curr Med Chem 13:1261-82. 2006
    ....
  13. ncbi 4-{(2R)-[3-Aminopropionylamido]-3-(2,4-dichlorophenyl)propionyl}-1-{2-[(2-thienyl)ethylaminomethyl]phenyl}piperazine as a potent and selective melanocortin-4 receptor antagonist--design, synthesis, and characterization
    Chen Chen
    Neurocrine Biosciences, Inc 12790 El Camino Real, San Diego, CA 92130, USA
    J Med Chem 47:6821-30. 2004
    ..9 in the inhibition of alpha-MSH-stimulated cAMP accumulation. 10 also penetrated into the brain when dosed intravenously in rats...
  14. ncbi Design of 2,5-dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)-7-dipropylaminopyrazolo[1,5-a]pyrimidine (NBI 30775/R121919) and structure--activity relationships of a series of potent and orally active corticotropin-releasing factor receptor antagonists
    Chen Chen
    Neurocrine Biosciences, Inc, 10555 Sciences Center Drive, San Diego, California 92121, USA
    J Med Chem 47:4787-98. 2004
    ..26 h was developed into a clinical compound and exhibited efficacy in patients with major depression...
  15. ncbi Some pharmacokinetic aspects of the lipophilic terfenadine and zwitterionic fexofenadine in humans
    Chen Chen
    Department of Medicinal Chemistry, Neurocrine Biosciences, Inc, San Diego, California 92130, USA
    Drugs R D 8:301-14. 2007
    ....
  16. ncbi Physicochemical, pharmacological and pharmacokinetic properties of the zwitterionic antihistamines cetirizine and levocetirizine
    Chen Chen
    Department of Medicinal Chemistry, Neurocrine Biosciences, Inc, 12790 El Camino Real, San Diego, CA 92130, USA
    Curr Med Chem 15:2173-91. 2008
    ..Therefore, cetirizine, or its single isomer levocetirizine, might serve a good example for medicinal chemists to design zwitterionic drugs from a basic, acidic or neutral lead molecule for peripheral biological targets...
  17. ncbi Discovery of a series of nonpeptide small molecules that inhibit the binding of insulin-like growth factor (IGF) to IGF-binding proteins
    C Chen
    Neurocrine Biosciences, Inc, 10555 Science Center Drive, San Diego, California 92121, USA
    J Med Chem 44:4001-10. 2001
    ..These results point to the feasibility of developing orally active therapeutics to treat IGF-responsive diseases by optimization of the lead molecules 1 and 2...
  18. ncbi 1-Alkyl-3-amino-5-aryl-1H-[1,2,4]triazoles: novel synthesis via cyclization of N-acyl-S-methylisothioureas with alkylhydrazines and their potent corticotropin-releasing factor-1 (CRF(1)) receptor antagonist activities
    C Chen
    Neurocrine Biosciences, Inc, 10555 Science Centre Drive, San Diego, CA 92121, USA
    Bioorg Med Chem Lett 11:3165-8. 2001
    ..Among them, 1-methyl-3-[N-bis(cyclopropyl)methyl-N-propylamino]-5-(2,4-dichlorophenyl)-1H-[1,2,4]triazole 7a had the best binding affinity for the CRF(1) receptor (K(i)=9 nM)...
  19. ncbi Identification and characterization of pyrrolidine diastereoisomers as potent functional agonists and antagonists of the human melanocortin-4 receptor
    Chen Chen
    Department of Medicinal Chemistry, Neurocrine Biosciences, Inc, 12790 El Camino Real, San Diego, CA 92130, USA
    Bioorg Med Chem Lett 18:129-36. 2008
    ..7 and an IC50 of 64 nM. Both compounds were highly selective over other melanocortin receptor subtypes. The MC4R agonist 13b-1 also demonstrated efficacy in a diet-induced obesity model in rats...
  20. ncbi Synthesis and initial structure-activity relationships of a novel series of imidazolo[1,2-a]pyrimid-5-ones as potent GnRH receptor antagonists
    Keith M Wilcoxen
    Department of Medicinal Chemistry, Neurocrine Biosciences, Inc, 10555 Science Center Drive, San Diego, CA 92121, USA
    Bioorg Med Chem Lett 12:2179-83. 2002
    ..Compounds with good potency (e.g., 10e, K(i)=7.5 nM) were prepared by introduction of a 2-(2-pyridyl)ethyl at the basic nitrogen and a 3-pentyl ester at the 6-position of the bicyclic core...
  21. ncbi Species selectivity of nonpeptide antagonists of the gonadotropin-releasing hormone receptor is determined by residues in extracellular loops II and III and the amino terminus
    Greg J Reinhart
    Department of Endocrinology, Neurocrine Biosciences Inc, 10555 Science Center Drive, San Diego, CA 92121, USA
    J Biol Chem 279:34115-22. 2004
    ....
  22. ncbi Design, synthesis, in vitro, and in vivo characterization of phenylpiperazines and pyridinylpiperazines as potent and selective antagonists of the melanocortin-4 receptor
    Joe A Tran
    Department of Medicinal Chemistry, Neurocrine Biosciences, Inc, 12790 El Camino Real, San Diego, California 92130, USA
    J Med Chem 50:6356-66. 2007
    ..Our results provided further evidence that a potent and selective MC4R antagonist with appropriate pharmacokinetic properties might potentially be useful for the treatment of cancer cachexia...
  23. ncbi Identification of a nonpeptide ligand that releases bioactive insulin-like growth factor-I from its binding protein complex
    X J Liu
    Department of Peptide Chemistry, Neurocrine Biosciences, Inc, San Diego, California 92121, USA
    J Biol Chem 276:32419-22. 2001
    ..Thus, NBI-31772 could serve as a valuable lead molecule for the design of novel therapeutics to treat diabetes and other IGF-responsive diseases...
  24. ncbi 3-[(2R)-Amino-2-phenylethyl]-1-(2,6-difluorobenzyl)-5-(2-fluoro-3-methoxyphenyl)- 6-methylpyrimidin-2,4-dione (NBI 42902) as a potent and orally active antagonist of the human gonadotropin-releasing hormone receptor. Design, synthesis, and in vitro and in
    Fabio C Tucci
    Department of Medicinal Chemistry, Neurocrine Biosciences, Inc, 12790 El Camino Real, San Diego, California 92130, USA
    J Med Chem 48:1169-78. 2005
    ..These results demonstrate that compounds from this series of uracils are potent GnRH antagonists with good oral bioavailability and efficacy in nonhuman primates...
  25. doi Characterization of thien-2-yl 1S,2R-milnacipran analogues as potent norepinephrine/serotonin transporter inhibitors for the treatment of neuropathic pain
    Brian Dyck
    Department of Medicinal Chemistry, Neurocrine Biosciences, Inc, 12790 El Camino Real, San Diego, California 92130, USA
    J Med Chem 51:7265-72. 2008
    ..In addition, 5c displayed desirable pharmacokinetic properties in several species, including high oral availability and significant brain penetration...
  26. doi Design and synthesis of 3-arylpyrrolidine-2-carboxamide derivatives as melanocortin-4 receptor ligands
    Joe A Tran
    Department of Medicinal Chemistry, Neurocrine Biosciences, Inc, 12790 El Camino Real, San Diego, CA 92130, USA
    Bioorg Med Chem Lett 18:1931-8. 2008
    ..It was found that the 2R,3R-pyrrolidine isomer possessed the most potent affinity among the four stereoisomers...
  27. ncbi Pyrrolidinones as orally bioavailable antagonists of the human melanocortin-4 receptor with anti-cachectic activity
    Joe A Tran
    Department of Medicinal Chemistry, Neurocrine Biosciences Inc, San Diego, CA 92130, USA
    Bioorg Med Chem 15:5166-76. 2007
    ..These compounds showed high potencies and selectivities, and several of them had good oral bioavailabilities. In addition, 12e demonstrated in vivo efficacy in a murine cachexia model...
  28. ncbi Molecular interactions of nonpeptide agonists and antagonists with the melanocortin-4 receptor
    Beth A Fleck
    Department of Pharmacology, Neurocrine Biosciences Inc, 12790 El Camino Real, San Diego, California 92130, USA
    Biochemistry 44:14494-508. 2005
    ..Furthermore, the strength of interaction with the aromatic pocket, and potentially the acidic pocket, controls the signaling efficacy of the ligand...
  29. doi Zwitterionic uracil derivatives as potent GnRH receptor antagonists with improved pharmaceutical properties
    Colin F Regan
    Department of Medicinal Chemistry, Neurocrine Biosciences, Inc, 12780 El Camino Real, San Diego, CA 92130, USA
    Bioorg Med Chem Lett 18:4503-7. 2008
    ..A novel series of potent zwitterionic uracil GnRH antagonists were discovered that showed reduced liability for CYP3A4 enzyme inhibition...
  30. doi Structure-activity relationship studies on a series of piperazinebenzylalcohols and their ketone and amine analogs as melanocortin-4 receptor ligands
    Dragan Marinkovic
    Department of Medicinal Chemistry, Neurocrine Biosciences, Inc, 12790 El Camino Real, San Diego, CA 92121, USA
    Bioorg Med Chem Lett 18:4817-22. 2008
    ..Several benzylalcohols such as 14a and 14g displayed low nanomolar binding affinities (K(i)<10 nM), and high selectivities over other melanocortin receptor subtypes...
  31. ncbi A novel synthesis of 2-arylpyrrolo[1,2-a]pyrimid-7-ones and their structure-activity relationships as potent GnRH receptor antagonists
    Yun Fei Zhu
    Neurocrine Biosciences, Inc, 10555 Science Center Drive, San Diego, CA 92121, USA
    Bioorg Med Chem Lett 12:403-6. 2002
    ..These intermediates were further modified at positions 1, 2, 4 and 6 to afford a series of potent GnRH antagonists with low nanomolar K(i) values...
  32. doi 5-Aryluracils as potent GnRH antagonists-Characterization of atropisomers
    Liren Zhao
    Department of Medicinal Chemistry, Neurocrine Biosciences, Inc, 12790 El Camino Real, San Diego, CA 92129, USA
    Bioorg Med Chem Lett 18:3344-9. 2008
    ..It was found that the aR-atropisomer was much more potent than the aS-isomer based on the X-ray crystal structure of 3h-II...
  33. ncbi Pyrrolidinones as potent functional antagonists of the human melanocortin-4 receptor
    Wanlong Jiang
    Department of Medicinal Chemistry, Neurocrine Biosciences, Inc, 12790 El Camino Real, San Diego, CA 92130, USA
    Bioorg Med Chem Lett 17:5610-3. 2007
    ..In addition to their high binding affinities, these compounds displayed high functional potencies. 12a had a K(i) of 0.94 nM in binding and IC(50) of 21 nM in functional activity. 12a also demonstrated efficacy in a mouse cachexia model...
  34. ncbi Synthesis and characterization of trans-4-(4-chlorophenyl)pyrrolidine-3-carboxamides of piperazinecyclohexanes as ligands for the melanocortin-4 receptor
    Caroline W Chen
    Department of Medicinal Chemistry, Neurocrine Biosciences Inc, 12790 El Camino Real, San Diego, CA 92130, USA
    Bioorg Med Chem Lett 17:6825-31. 2007
    ..Compound 18 v was found to bind MC4R with potent affinity (K(i)=0.5 nM) and high selectivity over the other melanocortin subtypes and behaved as a functional antagonist (IC(50)=48 nM)...
  35. ncbi Synthesis of benzoylpyrimidines as antagonists of the corticotropin-releasing factor-1 receptor
    Thomas R Webb
    Department of Medicinal Chemistry and Department of Pharmacology, Neurocrine Bioscience, Inc, 10555 Science Center Drive, San Diego, CA 92121, USA
    Bioorg Med Chem Lett 14:3869-73. 2004
    ..Several synthetic routes were developed to explore the SAR of this series of compounds. Compounds such as 8d (K(i) = 15 nM) exhibited high binding affinities at the human CRF(1) receptor...
  36. doi Studies on the SAR and pharmacophore of milnacipran derivatives as monoamine transporter inhibitors
    Chen Chen
    Department of Medicinal Chemistry, Neurocrine Bioscience, Inc, 12790 El Camino Real, San Diego, CA 92130, USA
    Bioorg Med Chem Lett 18:1346-9. 2008
    ..A pharmacophore model was established based on the conformational analysis of milnacipran in aqueous solution using NMR techniques and was consistent with the SAR results...
  37. ncbi Propionylpiperazines as human melanocortin-4 receptor ligands
    Caroline W Chen
    Department of Medicinal Chemistry, Neurocrine Biosciences, Inc, 12790 El Camino Real, San Diego, CA 92130, USA
    Bioorg Med Chem Lett 16:4800-3. 2006
    ..In addition to its high potency and selectivity, R-11a had desirable pharmacokinetic properties including high brain penetration in mice...
  38. ncbi Pharmacological characterization of a novel nonpeptide antagonist of the human gonadotropin-releasing hormone receptor, NBI-42902
    R Scott Struthers
    Department of Endocrinology, Neurocrine Biosciences Inc, 12790 El Camino Real, San Diego, California 92130, USA
    Endocrinology 148:857-67. 2007
    ....
  39. ncbi Melanocortin-4 receptor antagonists as potential therapeutics in the treatment of cachexia
    Alan C Foster
    Neurocrine Biosciences Inc, San Diego, CA 92130, USA
    Curr Top Med Chem 7:1131-6. 2007
    ..Further development of such compounds is greatly anticipated as a potential means to combat the cachexia that results from chronic diseases such as cancer, AIDS, renal failure, liver failure, congestive heart failure and lung disease...
  40. ncbi Substituted NDP-MSH peptides paired with mutant melanocortin-4 receptors demonstrate the role of transmembrane 6 in receptor activation
    Beth A Fleck
    Departments of Pharmacology, Neurocrine Biosciences Inc, 12790 El Camino Real, San Diego, California 92130, USA
    Biochemistry 46:10473-83. 2007
    ..51) and F284(7.35). These findings refine the molecular basis for the mechanism of ligand-stimulated hMC4R activation and will be useful for the development of hMC4R agonists and antagonists...
  41. ncbi Syntheses of tetrahydrothiophenes and tetrahydrofurans and studies of their derivatives as melanocortin-4 receptor ligands
    Joe A Tran
    Department of Medicinal Chemistry, Neurocrine Biosciences, Inc, 12790 El Camino Real, San Diego, CA 92130, USA
    Bioorg Med Chem Lett 18:1124-30. 2008
    ..These five-membered ring constrained compounds possessed similar or lower potency compared to the acyclic analogs...
  42. doi Identification of 1S,2R-milnacipran analogs as potent norepinephrine and serotonin transporter inhibitors
    Junko Tamiya
    Department of Medicinal Chemistry, Neurocrine Bioscience, Inc, 12790 El Camino Real, San Diego, CA 92130, USA
    Bioorg Med Chem Lett 18:3328-32. 2008
    ..Thus, 15l exhibited IC(50) values of 1.7nM at NET and 25nM at SERT, which were, respectively, 20- and 13-fold more potent than 1S,2R-milnacipran 1-II...
  43. ncbi A novel synthesis of 7-aryl-8-fluoro-pyrrolo[1,2-a]pyrimid-4-ones as potent, stable GnRH receptor antagonists
    Fabio C Tucci
    Neurocrine Biosciences, Inc, San Diego, CA 92121, USA
    Bioorg Med Chem Lett 12:3491-5. 2002
    ..Amongst the compounds synthesized, we discovered some highly potent GnRH receptor antagonists (e.g., 12, K(i)=9 nM), which showed enhanced stability towards acidic physiological conditions compared to the des-fluoro analogues...
  44. ncbi Studies on the structure-activity relationship of the basic amine of phenylpiperazines as melanocortin-4 receptor antagonists
    Joe A Tran
    Department of Medicinal Chemistry, Neurocrine Biosciences, Inc, 12790 El Camino Real, San Diego, CA 92130, USA
    Med Chem 4:67-74. 2008
    ..Several potent compounds from this series possessed subnanomolar K(i) values in a competition binding assay...
  45. ncbi A convenient one-pot synthesis of asymmetric 1,3,5-triazine-2,4,6-triones and its application towards a novel class of gonadotropin-releasing hormone receptor antagonists
    Zhiqiang Guo
    Department of Medicinal Chemistry, Neurocrine Biosciences, Inc, 12790 El Camino Real, San Diego, CA 92130, USA
    Bioorg Med Chem Lett 15:693-8. 2005
    ..Subsequent alkylation with N-protected amino alcohols afforded the desired 1,3,5-triazine-2,4,6-triones in good yields. This methodology was applied to the synthesis of a chemical library acting as antagonists of the hGnRH receptor...
  46. ncbi Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor
    Stephen F Betz
    Department of Endocrinology, Neurocrine Biosciences, Inc, San Diego, California 92130, USA
    J Med Chem 49:637-47. 2006
    ..Moreover, the resulting receptor interaction maps provide a basis to begin to reconcile structure-activity relationships between various nonpeptide and peptide series and facilitate the design of improved therapeutic agents...
  47. ncbi Design and synthesis of 3-(2-pyridyl)pyrazolo[1,5-a]pyrimidines as potent CRF1 receptor antagonists
    Charles Q Huang
    Department of Medicinal Chemistry and Department of Pharmacology, Neurocrine Biosciences, Inc, 10555 Science Center Drive, San Diego, CA 92129, USA
    Bioorg Med Chem Lett 14:3943-7. 2004
    ..Several compounds such as 20c (K(i)=10 nM) exhibited good binding affinities at the CRF(1) receptor. In addition, 20c had adequate solubility in water...
  48. ncbi Identification of agonists and antagonists of the human melanocortin-4 receptor from piperazinebenzylamines
    Joe A Tran
    Department of Medicinal Chemistry, Neurocrine Biosciences, Inc, El Camino Real, San Diego, CA 92130, USA
    Bioorg Med Chem Lett 15:833-7. 2005
    ..3 and 4.5 nM, respectively. Interestingly, 12e was a full agonist with an EC(50) value of 31 nM, and 12l was a weak partial agonist (IA=17%) and functioned as an antagonist (IC(50)=300 nM)...
  49. ncbi Synthesis and structure-activity relationships of uracil derived human GnRH receptor antagonists: (R)-3-[2-(2-amino)phenethyl]-1-(2,6-difluorobenzyl)-6-methyluracils containing a substituted thiophene or thiazole at C-5
    Martin W Rowbottom
    Department of Medicinal Chemistry, Neurocrine Biosciences Inc, 12790 El Camino Real, San Diego, CA 92130, USA
    Bioorg Med Chem Lett 14:4967-73. 2004
    ..The best compound from the series had a binding affinity of 2 nM (K(i)) for the human GnRH receptor. A novel and convenient preparation of N-1-(2,6-difluorobenzyl)-6-methyluracil is also described...
  50. ncbi 3-(2-aminoalkyl)-1-(2,6-difluorobenzyl)-5- (2-fluoro-3-methoxyphenyl)-6-methyl-uracils as orally bioavailable antagonists of the human gonadotropin releasing hormone receptor
    Fabio C Tucci
    Departments of Medicinal Chemistry, Endocrinology, and Preclinical Development, Neurocrine Biosciences Inc, 10555 Science Center Drive, San Diego, CA 92121, USA
    J Med Chem 47:3483-6. 2004
    ..The compounds herein presented displayed superior metabolic stability than their predecessor molecules. Selected compounds from this series featured good oral bioavailability in mice and cynomolgus monkeys...
  51. ncbi Synthesis and structure-activity relationships of (R)-1-alkyl-3-[2-(2-amino)phenethyl]-5-(2-fluorophenyl)-6-methyluracils as human GnRH receptor antagonists
    Martin W Rowbottom
    Department of Medicinal Chemistry, Neurocrine Biosciences, Inc, 10555 Science Center Drive, San Diego, CA 92121, USA
    Bioorg Med Chem Lett 14:2269-74. 2004
    ..The best compound from the series had binding affinity of 0.7 nM (K(i) for the human GnRH receptor, which was 8-fold better than the 2,6-difluorobenzyl analog...
  52. ncbi Design, synthesis, and SAR of 2-dialkylamino-4-arylpyrimidines as potent and selective corticotropin-releasing factor(1) (CRF(1)) receptor antagonists
    Charles Q Huang
    Neurocrine Biosciences, Inc, 10555 Science Centre Drive, San Diego, CA 92121, USA
    Bioorg Med Chem Lett 14:2083-6. 2004
    ..SAR studies of this series resulted in the discovery of potent and selective antagonists 7b and 7n bearing a 4-(2,4,6-trisubstituted-phenyl) ring and a bulky 2-(N-bis(cyclopropane)methyl-N-propyl)amino group...
  53. ncbi Synthesis and structure-activity relationships of 1-arylmethyl-5-aryl-6-methyluracils as potent gonadotropin-releasing hormone receptor antagonists
    Zhiqiang Guo
    Department of Medicinal Chemistry, Neurocrine Biosciences, Inc, 10555 Science Center Drive, San Diego, California 92121, USA
    J Med Chem 47:1259-71. 2004
    ..This modification enabled us to make uracil compounds without the labile 2-pyridylethyl motif on the basic nitrogen while still maintained excellent potency against the hGnRH receptor...
  54. ncbi Synthesis and structure-activity relationships of 1-arylmethyl-3-(2-aminopropyl)-5-aryl-6-methyluracils as potent GnRH receptor antagonists
    Zhiqiang Guo
    Department of Medicinal Chemistry, Neurocrine Biosciences, Inc, 10555 Science Center Drive, San Diego, CA 92121, USA
    Bioorg Med Chem Lett 13:3311-5. 2003
    ..Introduction of a small methyl substituent at the beta-position from N3 of the uracil improved the GnRH binding potency by 5- to 10-fold. The best compound from the series had binding affinity of 5 nM (K(i)) to the human GnRH receptor...
  55. ncbi Synthesis and structure-activity relationships of thieno[2,3-d]pyrimidine-2,4-dione derivatives as potent GnRH receptor antagonists
    Zhiqiang Guo
    Department of Medicinal Chemistry, Neurocrine Biosciences, Inc, 10555 Science Center Drive, San Diego, CA 92121, USA
    Bioorg Med Chem Lett 13:3617-22. 2003
    ..SAR study of the 6-(4-aminophenyl) group suggests that hydrophobic substituents were preferred. The best compound from this series had binding affinity (K(i)) of 0.4 nM to the human GnRH receptor...
  56. ncbi Efficient synthesis of bicyclic oxazolino- and thiazolino[3,2-c]pyrimidine-5,7-diones and its application to the synthesis of GnRH antagonists
    Joseph Pontillo
    Department of Medicinal Chemistry, Neurocrine Biosciences, Inc, 12790 El Camino Real, San Diego, CA 92130, USA
    Bioorg Med Chem Lett 15:1407-11. 2005
    ..This reaction has been applied to the rapid syntheses of human gonadotropin-releasing hormone (hGnRH) receptor antagonists for SAR study, resulting in 13e with binding affinity in the low nanomolar range (4.5 nM)...
  57. ncbi Rational design, synthesis, and structure-activity relationships of aryltriazoles as novel corticotropin-releasing factor-1 receptor antagonists
    Richard F Lowe
    Department of Medicinal Chemistry, Neurocrine Biosciences Inc, 12790 El Camino Real, San Diego, CA 92130, USA
    J Med Chem 48:1540-9. 2005
    ..7 nM) to CRF(1) receptors with an IC(50) of 49 nM in a cAMP inhibition assay...
  58. ncbi Initial structure-activity relationship studies of a novel series of pyrrolo[1,2-a]pyrimid-7-ones as GnRH receptor antagonists
    Yun Fei Zhu
    Neurocrine Biosciences, Inc, 10555 Science Center Drive, San Diego, CA 92121, USA
    Bioorg Med Chem Lett 12:399-402. 2002
    ..2-(2-Methylaminoethyl)pyridine was discovered to be a key feature for generating active compounds. The best compound from the series had 25 nM (K(i)) binding affinity to human GnRH receptor...
  59. ncbi Practical asymmetric synthesis of alpha-branched 2-piperazinylbenzylamines by 1,2-additions of organometallic reagents to N-tert-butanesulfinyl imines
    Wanlong Jiang
    Department of Medicinal Chemistry, Neurocrine Biosciences, Inc, San Diego, California 92130, USA
    J Org Chem 70:8924-31. 2005
    ....
  60. ncbi Atropisomeric property of 1-(2,6-difluorobenzyl)-3-[(2R)-amino-2-phenethyl]-5-(2-fluoro-3-methoxyphenyl)-6-methyluracil
    Fabio C Tucci
    Department of Medicinal Chemistry, Neurocrine Biosciences, Inc, San Diego, CA 92130, USA
    Chirality 17:559-64. 2005
    ..4 kJ mol(-1)) was calculated using the Eyring equation. The diastereoisomer half-life at physiological temperature (37 degrees C) in aqueous media was estimated to be about 46 min...
  61. ncbi Potent and orally active non-peptide antagonists of the human melanocortin-4 receptor based on a series of trans-2-disubstituted cyclohexylpiperazines
    Fabio C Tucci
    Department of Medicinal Chemistry, Neurocrine Biosciences Inc, 12790 El Camino Real, San Diego, CA 92130, USA
    Bioorg Med Chem Lett 15:4389-95. 2005
    ..More importantly, when administered orally to mice (10 mg/kg), it led to statistically significant increases in food intake over a 24-h period...
  62. ncbi Synthesis of aryl-1,2,4-triazine-3,5-diones as antagonists of the gonadotropin-releasing hormone receptor
    Joseph Pontillo
    Department of Medicinal Chemistry, Neurocrine Biosciences Inc, 12790 El Camino Real, San Diego, CA 92130, USA
    Bioorg Med Chem Lett 15:4363-6. 2005
    ..Derivatives were synthesized and studied as gonadotropin-releasing hormone antagonists in an effort to understand structure-activity relationships of the monocyclic compounds...
  63. ncbi Structure-activity relationships of 1,3,5-triazine-2,4,6-triones as human gonadotropin-releasing hormone receptor antagonists
    Zhiqiang Guo
    Department of Medicinal Chemistry, Neurocrine Biosciences, Inc, 12790 El Camino Real, San Diego, CA 92130, USA
    Bioorg Med Chem Lett 15:3685-90. 2005
    ..SAR studies of 1,3,5-triazine-2,4,6-triones as human gonadotropin-releasing hormone receptor antagonists resulted in potent compounds. The best compound from the series had a binding affinity of 2 nM...
  64. ncbi Identification of 1-arylmethyl-3- (2-aminoethyl)-5-aryluracil as novel gonadotropin-releasing hormone receptor antagonists
    Yun Fei Zhu
    Department of Medicinal Chemistry, Neurocrine Biosciences, Inc, 10555 Science Center Drive, San Diego, California 92121, USA
    J Med Chem 46:2023-6. 2003
    ..Their syntheses and initial SAR are discussed herein. This is the first time that monocycle-based GnRH receptor antagonists are reported...
  65. ncbi Synthesis and structure-activity relationships of 1-arylmethyl-3-(1-methyl-2-amino)ethyl-5-aryl-6-methyluracils as antagonists of the human GnRH Receptor
    Fabio C Tucci
    Department of Medicinal Chemistry, Neurocrine Biosciences, Inc, 10555 Science Center Drive, San Diego, CA 92121, USA
    Bioorg Med Chem Lett 13:3317-22. 2003
    ..SAR studies were performed, which allowed the identification of derivatives (R)-9f, (R)-9h and (R)-12 as potent hGnRH antagonists (K(i)=20 nM)...
  66. doi Non-peptide gonadotropin-releasing hormone receptor antagonists
    Stephen F Betz
    Endocrinology and Metabolism, Neurocrine Biosciences, Inc, 12790 El Camino Real, San Diego, CA 92130, USA
    J Med Chem 51:3331-48. 2008
  67. ncbi Design, synthesis, and SAR studies on a series of 2-pyridinylpiperazines as potent antagonists of the melanocortin-4 receptor
    Joe A Tran
    Department of Medicinal Chemistry, Neurocrine Biosciences, Inc, 12790 El Camino Real, San Diego, CA 92130, USA
    Bioorg Med Chem Lett 16:3693-6. 2006
    ..A series of 2-pyridinylpiperazines derived from beta-Ala-(2,4-Cl)Phe dipeptide was synthesized for the study of their SARs and possible interactions with the MC4 receptor. Compounds such as 11k (Ki=6.5 nM) possessed high potency...
  68. ncbi Central administration of peptide and small molecule MC4 receptor antagonists induce hyperphagia in mice and attenuate cytokine-induced anorexia
    M A Joppa
    Neurocrine Biosciences Inc, San Diego, CA 92130, USA
    Peptides 26:2294-301. 2005
    ....
  69. ncbi IL-18-binding protein protects against lipopolysaccharide- induced lethality and prevents the development of Fas/Fas ligand-mediated models of liver disease in mice
    R Faggioni
    Amgen, Inc, Thousand Oaks, CA 91320, USA
    J Immunol 167:5913-20. 2001
    ..In conclusion, IL-18BP can be engineered and produced in recombinant form to generate an IL-18 inhibitor, IL-18BP-Fc, endowed with remarkable in vitro and in vivo properties of binding and neutralizing IL-18...
  70. ncbi Studies on the structure-activity relationship of bicifadine analogs as monoamine transporter inhibitors
    Mingzhu Zhang
    Department of Medicinal Chemistry, Neurocrine Biosciences, Inc, 12790 El Camino Real, San Diego, CA 92130, USA
    Bioorg Med Chem Lett 18:3682-6. 2008
    ..The norepinephrine-selective 2-thienyl compound S-6j was efficacious in a rodent pain model...
  71. ncbi The regulation of feeding and metabolic rate and the prevention of murine cancer cachexia with a small-molecule melanocortin-4 receptor antagonist
    Stacy Markison
    Department of Pediatrics, Mailcode CDRCP, 707 Southwest Gaines Road, Portland, Oregon 97239, USA
    Endocrinology 146:2766-73. 2005
    ..These data clearly demonstrate the potential of small molecule MC4-R antagonists in the treatment of cachexia and underscore the importance of melanocortin signaling in the development of this metabolic disorder...