Structure-activity relationships and pharmacokinetic evaluation of L-cystine diamides as L-cystine crystallization inhibitors for cystinuria

Longqin Hu, Haifa Albanyan, Jeffrey Yang, Xiangduan Tan, Yiling Wang, Min Yang, Xiaodi Zhong, Michael D. Ward, Amrik Sahota

Research output: Contribution to journalArticlepeer-review

Abstract

Cystinuria is a rare genetic disorder characterized by defective l-cystine reabsorption from the renal proximal tubule, resulting in abnormally high concentrations of L-cystine and subsequent l-cystine crystallization and stone formation in urine. l-Cystine diamides have shown great promise as inhibitors of l-cystine crystallization. The free α-amino groups in l-cystine diamides have previously been shown to be necessary for l-cystine crystallization inhibitory activity. In this study, three additional series of l-cystine diamide analogs were designed to explore further the structure-activity relationships for l-cystine crystallization inhibition. It has been demonstrated that the middle disulfide bond is required for optimal l-cystine crystallization inhibitory activity, and the only regions that can be modified are the two terminal amides. The presence of another basic amine 2–3 atoms away from the amide nitrogen is also critical for optimal activity. Disulfide exchange was found to be the main metabolic pathway resulting in the formation of two molecules of the active mixed disulfide metabolite from a single l-cystine diamide. l-Cystine diamides have the potential to be developed into a much-needed therapy for cystinuria. (Figure presented.).

Original languageEnglish (US)
JournalMedicinal Chemistry Research
DOIs
StateAccepted/In press - 2024

Keywords

  • Crystallization inhibition
  • Cystinuria
  • Kidney stones
  • l-cystine diamides

ASJC Scopus subject areas

  • General Pharmacology, Toxicology and Pharmaceutics
  • Organic Chemistry

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