Hu Longqin, Albanyan Haifa, Yang Jeffrey, Wang Yiling, Yang Min, Tan Xiangduan, Zhong Xiaodi, Ward Michael D, Sahota Amrik
Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, United States.
The Cancer Institute of New Jersey, New Brunswick, New Jersey 08901, United States.
ACS Med Chem Lett. 2024 Jun 6;15(7):1026-1031. doi: 10.1021/acsmedchemlett.4c00066. eCollection 2024 Jul 11.
Cystinuria, a rare genetic disorder, is characterized by defective l-cystine reabsorption from the renal proximal tubule, resulting in abnormally high concentrations of l-cystine and subsequent l-cystine crystallization in urine and stone formation in the urinary tract. Inhibition of l-cystine crystallization by l-cystine diamides such as LH708 () represents a promising new approach to prevent stone formation in patients with cystinuria. While shows promising efficacy and a good safety profile in a -knockout mouse model of cystinuria, further structural modification of led to the discovery of 8-l-cystinyl bis(1,8-diazaspiro[4.5]decane) (LH1753, ) incorporating a bioisosteric spiro bicyclic diamine 1,8-diazaspiro[4.5]decane for the -methylpiperazine terminal groups in as a promising candidate with being about 120× more potent than l-cystine dimethyl ester (CDME, ) and about 2× more potent than in inhibiting l-cystine crystallization. Furthermore, demonstrated good oral bioavailability and efficacy in preventing l-cystine stone formation in the -knockout mouse model of cystinuria.
胱氨酸尿症是一种罕见的遗传性疾病，其特征是肾近端小管对L-胱氨酸的重吸收存在缺陷，导致尿液中L-胱氨酸浓度异常升高，随后L-胱氨酸结晶并在尿路形成结石。用L-胱氨酸二酰胺（如LH708）抑制L-胱氨酸结晶是预防胱氨酸尿症患者结石形成的一种有前景的新方法。虽然LH708在胱氨酸尿症的β-敲除小鼠模型中显示出有前景的疗效和良好的安全性，但对LH708进行进一步的结构修饰后发现了8-L-胱氨酰双（1,8-二氮杂螺[4.5]癸烷）（LH1753），该化合物将生物电子等排体螺环双环二胺1,8-二氮杂螺[4.5]癸烷引入LH708的N-甲基哌嗪端基，作为一个有前景的候选药物，其抑制L-胱氨酸结晶的能力比L-胱氨酸二甲酯（CDME）强约120倍，比LH708强约2倍。此外，LH1753在胱氨酸尿症的β-敲除小鼠模型中显示出良好的口服生物利用度和预防L-胱氨酸结石形成的疗效。
