8-l-Cystinyl Bis(1,8-diazaspiro[4.5]decane) as an Orally Bioavailable l-Cystine Crystallization Inhibitor for Cystinuria.

ABSTRACT: 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 (2) represents a promising new approach to prevent stone formation in patients with cystinuria. While 2 shows promising in vivo efficacy and a good safety profile in a Slc3a1-knockout mouse model of cystinuria, further structural modification of 2 led to the discovery of 8-l-cystinyl bis(1,8-diazaspiro[4.5]decane) (LH1753, 3) incorporating a bioisosteric spiro bicyclic diamine 1,8-diazaspiro[4.5]decane for the N-methylpiperazine terminal groups in 2 as a promising candidate with 3 being about 120× more potent than l-cystine dimethyl ester (CDME, 1) and about 2× more potent than 2 in inhibiting l-cystine crystallization. Furthermore, 3 demonstrated good oral bioavailability and in vivo efficacy in preventing l-cystine stone formation in the Slc3a1-knockout mouse model of cystinuria.

SUBMITTER: Hu L 

PROVIDER: S-EPMC11247636 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature