Dataset Information

Targeting the BACE1 Active Site Flap Leads to a Potent Inhibitor That Elicits Robust Brain A? Reduction in Rodents.

ABSTRACT: By targeting the flap backbone of the BACE1 active site, we discovered 6-dimethylisoxazole-substituted biaryl aminothiazine 18 with 34-fold improved BACE1 inhibitory activity over the lead compound 1. The cocrystal structure of 18 bound to the active site indicated two hydrogen-bond interactions between the dimethylisoxazole and threonine 72 and glutamine 73 of the flap. Incorporation of the dimethylisoxazole substitution onto the related aminothiazine carboxamide series led to pyrazine-carboxamide 26 as a very potent BACE1 inhibitor (IC50 < 1 nM). This compound demonstrated robust brain A? reduction in rat dose-response studies. Thus, compound 26 may be useful in testing the amyloid hypothesis of Alzheimer's disease.

SUBMITTER: Wu YJ

PROVIDER: S-EPMC4789663 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Targeting the BACE1 Active Site Flap Leads to a Potent Inhibitor That Elicits Robust Brain Aβ Reduction in Rodents.

Wu Yong-Jin YJ Guernon Jason J Yang Fukang F Snyder Lawrence L Shi Jianliang J Mcclure Andrea A Rajamani Ramkumar R Park Hyunsoo H Ng Alicia A Lewis Hal H Chang ChiehYing C Camac Dan D Toyn Jeremy H JH Ahlijanian Michael K MK Albright Charles F CF Macor John E JE Thompson Lorin A LA

ACS medicinal chemistry letters 20160111 3

By targeting the flap backbone of the BACE1 active site, we discovered 6-dimethylisoxazole-substituted biaryl aminothiazine 18 with 34-fold improved BACE1 inhibitory activity over the lead compound 1. The cocrystal structure of 18 bound to the active site indicated two hydrogen-bond interactions between the dimethylisoxazole and threonine 72 and glutamine 73 of the flap. Incorporation of the dimethylisoxazole substitution onto the related aminothiazine carboxamide series led to pyrazine-carboxam ...[more]

PMID: 26985314

Dataset Information

Targeting the BACE1 Active Site Flap Leads to a Potent Inhibitor That Elicits Robust Brain A? Reduction in Rodents.

Publications

Targeting the BACE1 Active Site Flap Leads to a Potent Inhibitor That Elicits Robust Brain Aβ Reduction in Rodents.

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