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Li X.,Anacor Pharmaceuticals Inc. | Zhang S.,Anacor Pharmaceuticals Inc. | Zhang Y.-K.,Anacor Pharmaceuticals Inc. | Liu Y.,Anacor Pharmaceuticals Inc. | And 20 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2011

We have synthesized and evaluated a new series of acyclic P4-benzoxaborole-based HCV NS3 protease inhibitors. Structure-activity relationships were investigated, leading to the identification of compounds 5g and 17 with low nanomolar potency in the enzymatic and cell-based replicon assay. The linker-truncated compound 5j was found to exhibit improved absorption and oral bioavailability in rats, suggesting that further reduction of molecular weight and polar surface area could result in improved drug-like properties of this novel series. © 2011 Elsevier Ltd. All rights reserved.


Li X.,Anacor Pharmaceuticals Inc. | Zhang Y.-K.,Anacor Pharmaceuticals Inc. | Liu Y.,Anacor Pharmaceuticals Inc. | Ding C.Z.,Anacor Pharmaceuticals Inc. | And 29 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2010

We have designed and synthesized a novel series of α-amino cyclic boronates and incorporated them successfully in several acyclic templates at the P1 position. These compounds are inhibitors of the HCV NS3 serine protease, and structural studies show that they inhibit the NS3 protease by trapping the Ser-139 hydroxyl group in the active site. Synthetic methodologies and SARs of this series of compounds are described. © 2010 Elsevier Ltd.


Zhang Y.-K.,Anacor Pharmaceuticals Inc. | Plattner J.J.,Anacor Pharmaceuticals Inc. | Easom E.E.,Anacor Pharmaceuticals Inc. | Zhou Y.,Anacor Pharmaceuticals Inc. | And 10 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2015

A novel series of isoxazoline benzoxaborole small molecules was designed and synthesized for a structure-activity relationship (SAR) investigation to assess the ectoparasiticide activity against ticks and fleas. The study identified an orally bioavailable molecule, (S)-3,3-dimethyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol (38, AN8030), which was long lasting in dogs (t1/2 = 22 days). Compound 38 demonstrated 97.6% therapeutic effectiveness within 24 h of treatment, with residual efficacy of 95.3% against American dog ticks (Dermacentor variabilis) on day 30% and 100% against cat fleas (Ctenocephalides felis) on day 32 after a single oral dose at 50 mg/kg in dogs. © 2015 Elsevier Ltd. All rights reserved.


Li X.,Anacor Pharmaceuticals Inc. | Zhang Y.-K.,Anacor Pharmaceuticals Inc. | Liu Y.,Anacor Pharmaceuticals Inc. | Ding C.Z.,Anacor Pharmaceuticals Inc. | And 27 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2010

A novel series of P2-P4 macrocyclic HCV NS3/4A protease inhibitors with α-amino cyclic boronates as warheads at the P1 site was designed and synthesized. When compared to their linear analogs, these macrocyclic inhibitors exhibited a remarkable improvement in cell-based replicon activities, with compounds 9a and 9e reaching sub-micromolar potency in replicon assay. The SAR around α-amino cyclic boronates clearly established the influence of ring size, chirality and of the substitution pattern. Furthermore, X-ray structure of the co-crystal of inhibitor 9a and NS3 protease revealed that Ser-139 in the enzyme active site traps boron in the warhead region of 9a, thus establishing its mode of action. © 2010 Elsevier Ltd. All rights reserved.


Li X.,Anacor Pharmaceuticals Inc. | Zhang Y.-K.,Anacor Pharmaceuticals Inc. | Liu Y.,Anacor Pharmaceuticals Inc. | Zhang S.,Anacor Pharmaceuticals Inc. | And 19 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2010

HCV NS3/4A serine protease is essential for the replication of the HCV virus and has been a clinically validated target. A series of HCV NS3/4A protease inhibitors containing a novel acylsulfamoyl benzoxaborole moiety at the P1′ region was synthesized and evaluated. The resulting P1-P3 and P2-P4 macrocyclic inhibitors exhibited sub-nanomolar potency in the enzymatic assay and low nanomolar activity in the cell-based replicon assay. The in vivo PK evaluations of selected compounds are also described. © 2010 Elsevier Ltd. All rights reserved.


Ding C.Z.,Anacor Pharmaceuticals Inc. | Zhang Y.-K.,Anacor Pharmaceuticals Inc. | Li X.,Anacor Pharmaceuticals Inc. | Liu Y.,Anacor Pharmaceuticals Inc. | And 17 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2010

We disclose here a series of P4-benzoxaborole-substituted macrocyclic HCV protease inhibitors. These inhibitors are potent against HCV NS3 protease, their anti-HCV replicon potencies are largely impacted by substitutions on benzoxaborole ring system and P2 groups. P2 2-thiazole-isoquinoline provides best replicon potency. The in vitro SAR studies and in vivo PK evaluations of selected compounds are described herein. © 2010 Elsevier Ltd. All rights reserved.


PubMed | HIGH-TECH, Eli Lilly and Company, Anacor Pharmaceuticals Inc. and BioDuro LLC
Type: Journal Article | Journal: Bioorganic & medicinal chemistry letters | Year: 2015

A novel series of isoxazoline benzoxaborole small molecules was designed and synthesized for a structure-activity relationship (SAR) investigation to assess the ectoparasiticide activity against ticks and fleas. The study identified an orally bioavailable molecule, (S)-3,3-dimethyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol (38, AN8030), which was long lasting in dogs (t1/2=22 days). Compound 38 demonstrated 97.6% therapeutic effectiveness within 24 h of treatment, with residual efficacy of 95.3% against American dog ticks (Dermacentor variabilis) on day 30% and 100% against cat fleas (Ctenocephalides felis) on day 32 after a single oral dose at 50 mg/kg in dogs.

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