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

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.