Publications by authors named "Dongpei Wu"

15 Publications

  • Page 1 of 1

Discovery of Imidazo[1,2-]pyrazines and Pyrazolo[1,5-]pyrimidines as TARP γ-8 Selective AMPAR Negative Modulators.

ACS Med Chem Lett 2019 Mar 26;10(3):267-272. Epub 2018 Dec 26.

Janssen Research & Development L.L.C., 3210 Merryfield Row, San Diego, California 92121 United States.

This report discloses the discovery and characterization of imidazo[1,2-]pyrazines and pyrazolo[1,5-]pyrimidines as selective negative modulators of α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors (AMPARs) associated with transmembrane AMPAR regulatory protein γ-8. Imidazopyrazine was initially identified as a promising γ-8 selective high-throughput screening hit, and subsequent structure-activity relationship optimization yielded subnanomolar, brain penetrant leads. Replacement of the imidazopyrazine core with an isosteric pyrazolopyrimidine scaffold improved microsomal stability and efflux liabilities to provide , JNJ-61432059. Following oral administration, exhibited time- and dose-dependent AMPAR/γ-8 receptor occupancy in mouse hippocampus, which resulted in robust seizure protection in corneal kindling and pentylenetetrazole (PTZ) anticonvulsant models.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsmedchemlett.8b00599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6421542PMC
March 2019

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 gonadotropin-releasing hormone receptor.

J Med Chem 2008 Dec;51(23):7478-85

Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, California 92130, USA.

The discovery of novel uracil phenylethylamines bearing a butyric acid as potent human gonadotropin-releasing hormone receptor (hGnRH-R) antagonists is described. A major focus of this optimization was to improve the CYP3A4 inhibition liability of these uracils while maintaining their GnRH-R potency. 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}butyric acid sodium salt, 10b (elagolix), was identified as a potent and selective hGnRH-R antagonist. 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jm8006454DOI Listing
December 2008

Synthesis and structure-activity relationships of selective norepinephrine reuptake inhibitors (sNRI) with improved pharmaceutical characteristics.

Bioorg Med Chem Lett 2008 Dec 7;18(23):6151-5. Epub 2008 Oct 7.

Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, CA 92130, USA.

The design synthesis and SAR of a series of chiral ring-constrained norepinephrine reuptake inhibitors with improved physicochemical properties is described. Typical compounds are potent (IC(50)s<10 nM), selective against the other monoamine transporters, weak CYP2D6 inhibitors (IC(50)s>1 microM) and stable to oxidation by human liver microsomes. In addition, the compounds exhibit a favorable polarity profile.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2008.10.013DOI Listing
December 2008

Discovery of a potent, selective, and less flexible selective norepinephrine reuptake inhibitor (sNRI).

Bioorg Med Chem Lett 2008 Jul 20;18(14):4224-7. Epub 2008 May 20.

Department of Medicinal Chemistry, Neurocrine Biosciences Inc. 12790 El Camino Real, San Diego, CA 92130, USA.

The design, synthesis, and SAR of a series of ring-constrained norepinephrine reuptake inhibitors are described. A substantially rigid inhibitor with potent functional activity at the transporter (IC(50)=8 nM) was used to develop a model for the distance and orientation of key features necessary for interaction with the norepinephrine transporter (NET).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2008.05.057DOI Listing
July 2008

Potent and orally bioavailable zwitterion GnRH antagonists with low CYP3A4 inhibitory activity.

Bioorg Med Chem Lett 2008 Jun 26;18(11):3301-5. Epub 2008 Apr 26.

Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, CA 92130, USA.

Incorporation of a carboxylic acid into a series of uracil derivatives as hGnRH-R antagonists resulted in a significant reduction of CYP3A4 inhibitory activity. 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2008.04.036DOI Listing
June 2008

5-Aryluracils as potent GnRH antagonists-Characterization of atropisomers.

Bioorg Med Chem Lett 2008 Jun 15;18(11):3344-9. Epub 2008 Apr 15.

Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, CA 92129, USA.

Optimization of a series of uracils bearing a 2-fluoro- or 2-chloro-3-methoxyphenyl group at the 5-position resulted in compounds such as 3d and 3f with subnanomolar binding affinity at the human GnRH receptor. While the 2-fluoro-3-methoxyphenyl compound 3a was characterized as a mixture of interchangeable atropisomers, the diastereoisomers of 2-chloro-3-methoxyphenyl analogs were separated. 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2008.04.029DOI Listing
June 2008

Synthesis and structure-activity relationships of retro bis-aminopyrrolidine urea (rAPU) derived small-molecule antagonists of the melanin-concentrating hormone receptor-1 (MCH-R1). Part 2.

Bioorg Med Chem Lett 2006 Sep 7;16(18):4922-30. Epub 2006 Jul 7.

Department of Medicinal Chemistry, Neurocrine Biosciences Inc., 12790 El Camino Real, San Diego, CA 92130, USA.

The design, synthesis, and SAR of a series of retro bis-aminopyrrolidine ureas are described. Compounds from this series exhibited considerable binding affinity (Ki = 1 nM) and functional activity at MCH-R1, acceptable CYP2D6 inhibition, and good rat brain exposure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2006.06.049DOI Listing
September 2006

Synthesis and structure-activity relationships of retro bis-aminopyrrolidine urea (rAPU) derived small-molecule antagonists of the melanin-concentrating hormone receptor-1 (MCH-R1). Part 1.

Bioorg Med Chem Lett 2006 Sep 30;16(17):4450-7. Epub 2006 Jun 30.

Department of Medicinal Chemistry, Neurocrine Biosciences Inc., San Diego, CA 92130, USA.

The design, synthesis, and SAR of a series of retro bis-aminopyrrolidine ureas are described. Compounds from this series exhibited potent binding affinity and functional activity at MCH-R1, and good oral bioavailability in rat.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2006.06.045DOI Listing
September 2006

Synthesis of aryl-1,2,4-triazine-3,5-diones as antagonists of the gonadotropin-releasing hormone receptor.

Bioorg Med Chem Lett 2005 Oct;15(19):4363-6

Department of Medicinal Chemistry, Neurocrine Biosciences Inc., 12790 El Camino Real, San Diego, CA 92130, USA.

Several efficient synthetic routes for 2-, 4-, and 6-aryl-1,2,4-triazine-3,5-diones were developed. Derivatives were synthesized and studied as gonadotropin-releasing hormone antagonists in an effort to understand structure-activity relationships of the monocyclic compounds.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2005.06.057DOI Listing
October 2005

Structure-activity relationships of 1,3,5-triazine-2,4,6-triones as human gonadotropin-releasing hormone receptor antagonists.

Bioorg Med Chem Lett 2005 Aug;15(16):3685-90

Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, CA 92130, USA.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2005.05.038DOI Listing
August 2005

Uracils as potent antagonists of the human gonadotropin-releasing hormone receptor without atropisomers.

Bioorg Med Chem Lett 2005 May;15(10):2519-22

Department of Medicinal Chemistry, Neurocrine Biosciences, Inc. 12790 El Camino Real, San Diego, CA 92130, USA.

Uracil derivatives were designed and synthesized to avoid atropisomers observed in the 6-methyluracils as antagonists of the human GnRH receptor. Optimization at the 1- and 5-positions of the uracil resulted in potent compounds such as 24 (Ki=0.45 nM).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2005.03.057DOI Listing
May 2005

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.

Bioorg Med Chem Lett 2005 Feb;15(3):693-8

Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, CA 92130, USA.

A convenient one-pot synthetic route was developed for the preparation of asymmetric 1,3-dialkyl-1,3,5-triazine-2,4,6-triones from readily available alkyl- or aryl-isocyanates, primary amines and N-chlorocarbonyl isocyanate in excellent yields. 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2004.11.026DOI Listing
February 2005

Synthesis and structure-activity relationships of thieno[2,3-d]pyrimidine-2,4-dione derivatives as potent GnRH receptor antagonists.

Bioorg Med Chem Lett 2003 Oct;13(20):3617-22

Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 10555 Science Center Drive, San Diego, CA 92121, USA.

The synthesis and SAR studies of thieno[2,3-d]pyrimidine-2,4-diones as human GnRH receptor antagonists to treat reproductive diseases are discussed. It was found that the 2-(2-pyridyl)ethyl group on the 5-aminomethyl functionality of the core structure was a key feature for good receptor binding activity. 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/s0960-894x(03)00746-7DOI Listing
October 2003

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.

J Med Chem 2003 Apr;46(9):1769-72

Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 10555 Science Center Drive, San Diego, California 92121, USA.

SAR studies of 7-phenylpyrrolo[1,2-a]pyrimid-4-ones 1 and 2, and 2-phenylimidazolo[1,2-a]pyrimidines 3 and 4, as nonpeptide human GnRH receptor antagonists, lead us to believe that the aromatic ring at position-2 of 4 is no longer crucial for the binding once an aryl group is incorporated at postion-6. 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jm0205402DOI Listing
April 2003