吡唑啉酮 - 哌啶二肽生长激素促分泌素（GHSs）。卡莫瑞林的发现。
Pyrazolinone-piperidine dipeptide growth hormone secretagogues (GHSs). Discovery of capromorelin.
作者信息
Carpino Philip A, Lefker Bruce A, Toler Steven M, Pan Lydia C, Hadcock John R, Cook Ewell R, DiBrino Joseph N, Campeta Anthony M, DeNinno Shari L, Chidsey-Frink Kristin L, Hada William A, Inthavongsay John, Mangano F Michael, Mullins Michelle A, Nickerson David F, Ng Oicheng, Pirie Christine M, Ragan John A, Rose Colin R, Tess David A, Wright Ann S, Yu Li, Zawistoski Michael P, DaSilva-Jardine Paul A, Wilson Theresa C, Thompson David D
机构信息
Pfizer Global Research and Development, Groton Labs, MS8220-3004, Eastern Point Rd, CT 06340, Groton, USA.
出版信息
Bioorg Med Chem. 2003 Feb 20;11(4):581-90. doi: 10.1016/s0968-0896(02)00433-9.
Novel pyrazolinone-piperidine dipeptide derivatives were synthesized and evaluated as growth hormone secretagogues (GHSs). Two analogues, capromorelin (5, CP-424391-18, hGHS-R1a K(i)=7 nM, rat pituicyte EC(50)=3 nM) and the des-methyl analogue 5c (hGHS-R1a K(i)=17 nM, rat pituicyte EC(50)=3 nM), increased plasma GH levels in an anesthesized rat model, with ED(50) values less than 0.05 mg/kg iv. Capromorelin showed enhanced intestinal absorption in rodent models and exhibited superior pharmacokinetic properties, including high bioavailabilities in two animal species [F(rat)=65%, F(dog)=44%]. This short-duration GHS was orally active in canine models and was selected as a development candidate for the treatment of musculoskeletal frailty in elderly adults.
合成了新型吡唑啉酮 - 哌啶二肽衍生物，并将其作为生长激素促分泌剂（GHSs）进行评估。两种类似物，卡莫瑞林（5，CP - 424391 - 18，人GHS - R1a K(i)=7 nM，大鼠垂体细胞EC(50)=3 nM）和去甲基类似物5c（人GHS - R1a K(i)=17 nM，大鼠垂体细胞EC(50)=3 nM），在麻醉大鼠模型中可提高血浆生长激素水平，静脉注射的ED(50)值小于0.05 mg/kg。卡莫瑞林在啮齿动物模型中显示出增强的肠道吸收，并表现出优异的药代动力学性质，包括在两种动物物种中的高生物利用度[大鼠F = 65%，犬F = 44%]。这种短效GHS在犬模型中口服有活性，并被选为治疗老年成人肌肉骨骼虚弱的开发候选药物。
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