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Discovery of VU0467485/AZ13713945: An M4 PAM Evaluated as a Preclinical Candidate for the Treatment of Schizophrenia.
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2017-02-16 , DOI: 10.1021/acsmedchemlett.6b00461 Michael R Wood 1 , Meredith J Noetzel 1 , Bruce J Melancon 1 , Michael S Poslusney 2 , Kellie D Nance 2 , Miguel A Hurtado 2 , Vincent B Luscombe 1 , Rebecca L Weiner 1 , Alice L Rodriguez 1 , Atin Lamsal 1 , Sichen Chang 1 , Michael Bubser 1 , Anna L Blobaum 1 , Darren W Engers 1 , Colleen M Niswender 3 , Carrie K Jones 3 , Nicholas J Brandon 4 , Michael W Wood 4 , Mark E Duggan 4 , P Jeffrey Conn 3 , Thomas M Bridges 1 , Craig W Lindsley 1
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2017-02-16 , DOI: 10.1021/acsmedchemlett.6b00461 Michael R Wood 1 , Meredith J Noetzel 1 , Bruce J Melancon 1 , Michael S Poslusney 2 , Kellie D Nance 2 , Miguel A Hurtado 2 , Vincent B Luscombe 1 , Rebecca L Weiner 1 , Alice L Rodriguez 1 , Atin Lamsal 1 , Sichen Chang 1 , Michael Bubser 1 , Anna L Blobaum 1 , Darren W Engers 1 , Colleen M Niswender 3 , Carrie K Jones 3 , Nicholas J Brandon 4 , Michael W Wood 4 , Mark E Duggan 4 , P Jeffrey Conn 3 , Thomas M Bridges 1 , Craig W Lindsley 1
Affiliation
Herein, we report the structure-activity relationships within a series of potent, selective, and orally bioavailable muscarinic acetylcholine receptor 4 (M4) positive allosteric modulators (PAMs). Compound 6c (VU0467485) possesses robust in vitro M4 PAM potency across species and in vivo efficacy in preclinical models of schizophrenia. Coupled with an attractive DMPK profile and suitable predicted human PK, 6c (VU0467485) was evaluated as a preclinical development candidate.
中文翻译：
VU0467485 / AZ13713945的发现：被评估为治疗精神分裂症的临床前候选药物的M4 PAM。
在这里，我们报告一系列有效的，选择性的和口服生物利用毒蕈碱乙酰胆碱受体4（M4）变构调节剂（PAMs）中的结构活性关系。在精神分裂症的临床前模型中，化合物6c（VU0467485）具有跨物种的强大体外M4 PAM效能和体内功效。结合有吸引力的DMPK谱和合适的预测人PK，将6c（VU0467485）评估为临床前开发候选药物。
更新日期：2016-12-20
中文翻译：
VU0467485 / AZ13713945的发现：被评估为治疗精神分裂症的临床前候选药物的M4 PAM。
在这里，我们报告一系列有效的，选择性的和口服生物利用毒蕈碱乙酰胆碱受体4（M4）变构调节剂（PAMs）中的结构活性关系。在精神分裂症的临床前模型中，化合物6c（VU0467485）具有跨物种的强大体外M4 PAM效能和体内功效。结合有吸引力的DMPK谱和合适的预测人PK，将6c（VU0467485）评估为临床前开发候选药物。
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