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Structure-Based Drug Discovery of N-((R)-3-(7-Methyl-1H-indazol-5-yl)-1-oxo-1-(((S)-1-oxo-3-(piperidin-4-yl)-1-(4-(pyridin-4-yl)piperazin-1-yl)propan-2-yl)amino)propan-2-yl)-2'-oxo-1',2'-dihydrospiro[piperidine-4,4'-pyrido[2,3-d][1,3]oxazine]-1-carboxamide (HTL22562): A Calcitonin Gene-Related Peptide Receptor Antagonist for Acute Treatment of Migraine.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-06-19 , DOI: 10.1021/acs.jmedchem.0c01003 Sarah J Bucknell 1 , Mark A Ator 2 , Alastair J H Brown 1 , Jason Brown 1 , Andrew D Cansfield 1 , Julie E Cansfield 1 , John A Christopher 1 , Miles Congreve 1 , Gabriella Cseke 1 , Francesca Deflorian 1 , Christopher R Jones 1 , Jonathan S Mason 1 , M Alistair O'Brien 1 , Gregory R Ott 2 , Mark Pickworth 1 , Stacey M Southall 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-06-19 , DOI: 10.1021/acs.jmedchem.0c01003 Sarah J Bucknell 1 , Mark A Ator 2 , Alastair J H Brown 1 , Jason Brown 1 , Andrew D Cansfield 1 , Julie E Cansfield 1 , John A Christopher 1 , Miles Congreve 1 , Gabriella Cseke 1 , Francesca Deflorian 1 , Christopher R Jones 1 , Jonathan S Mason 1 , M Alistair O'Brien 1 , Gregory R Ott 2 , Mark Pickworth 1 , Stacey M Southall 1
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Structure-based drug design enabled the discovery of 8, HTL22562, a calcitonin gene-related peptide (CGRP) receptor antagonist. The structure of 8 complexed with the CGRP receptor was determined at a 1.6 Å resolution. Compound 8 is a highly potent, selective, metabolically stable, and soluble compound suitable for a range of administration routes that have the potential to provide rapid systemic exposures with resultant high levels of receptor coverage (e.g., subcutaneous). The low lipophilicity coupled with a low anticipated clinically efficacious plasma exposure for migraine also suggests a reduced potential for hepatotoxicity. These properties have led to 8 being selected as a clinical candidate for acute treatment of migraine.
中文翻译：
N-（（R）-3-（7-甲基-1H-吲唑-5-基）-1-氧代-1-（（（S）-1-氧代-3-（哌啶- 4-基）-1-（4-（吡啶-4-基）哌嗪-1-基）丙-2-基）氨基）丙-2-基）-2'-氧代-1'，2'-二氢螺[哌啶-4,4'-吡啶并[2,3-d] [1,3]恶嗪] -1-羧酰胺（HTL22562）：降钙素基因相关肽受体拮抗剂，用于急性偏头痛的治疗。
基于结构的药物设计使人们能够发现降钙素基因相关肽（CGRP）受体拮抗剂HTL22562 8。与CGRP受体复合的8的结构以1.6的分辨率确定。化合物8是高效的，选择性的，代谢稳定的和可溶的化合物，适用于一系列给药途径，这些途径可能提供快速的全身性暴露，并导致高水平的受体覆盖（例如皮下）。低的亲脂性加上偏头痛的预期的临床上有效的血浆暴露量也低，提示肝毒性潜力降低。这些特性已导致8人被选作偏头痛急性治疗的临床候选者。
更新日期：2020-07-23
中文翻译：
N-（（R）-3-（7-甲基-1H-吲唑-5-基）-1-氧代-1-（（（S）-1-氧代-3-（哌啶- 4-基）-1-（4-（吡啶-4-基）哌嗪-1-基）丙-2-基）氨基）丙-2-基）-2'-氧代-1'，2'-二氢螺[哌啶-4,4'-吡啶并[2,3-d] [1,3]恶嗪] -1-羧酰胺（HTL22562）：降钙素基因相关肽受体拮抗剂，用于急性偏头痛的治疗。
基于结构的药物设计使人们能够发现降钙素基因相关肽（CGRP）受体拮抗剂HTL22562 8。与CGRP受体复合的8的结构以1.6的分辨率确定。化合物8是高效的，选择性的，代谢稳定的和可溶的化合物，适用于一系列给药途径，这些途径可能提供快速的全身性暴露，并导致高水平的受体覆盖（例如皮下）。低的亲脂性加上偏头痛的预期的临床上有效的血浆暴露量也低，提示肝毒性潜力降低。这些特性已导致8人被选作偏头痛急性治疗的临床候选者。
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