Design, synthesis, and evaluation of L-cystine diamides as L-cystine crystallization inhibitors for cystinuria

To overcome the chemical and metabolic stability issues of L-cystine dimethyl ester (CDME) and L-cystine methyl ester (CME), a series of L-cystine diamides with or without N^α-methylation was designed, synthesized, and evaluated for their inhibitory activity of L-cystine crystallization. L-Cystine diamides 2a–i without N^α-methylation were found to be potent inhibitors of L-cystine crystallization while N^α-methylation of L-cystine diamides resulted in derivatives 3b–i devoid of any inhibitory activity of L-cystine crystallization. Computational modeling indicates that N^α-methylation leads to significant decrease in binding of the L-cystine diamides to L-cystine crystal surface. Among the L-cystine diamides 2a–i, L-cystine bismorpholide (CDMOR, LH707, 2g) and L-cystine bis(N′-methylpiperazide) (CDNMP, LH708, 2h) are the most potent inhibitors of L-cystine crystallization.