| Nitric oxide synthase (NOS) has attracted much interest in the field of medicinal chemistry due to its wide range of physiological functions. NOS exists as three distinct isoforms: endothelial (eNOS), inducible (iNOS), and neuronal (nNOS). Nitric oxide (NO) derived from each isoform has been associated with a variety of disease states. Overproduction of NO form nNOS has been implicated in several pathological conditions, such as, stroke, migraines, Alzheimer's and Parkinson's disease. As a result, selective inhibition of nNOS could be therapeutically useful. A breakthrough was observed when a series of dipeptide amide inhibitors was synthesized and tested against all three isoforms (Huang, H.; et al. J. Med. Chem. 1999, 42, 3147-3153). Among these dipeptides, L-ArgNO2-L-Dbu-NH2 exhibited an outstanding inhibition landscape. L-ArgNO2- L-Dbu-NH2 was extremely potent (Ki = 0.13 muM), and showed excellent selectivity (1538-fold) for nNOS over eNOS and good selectivity (192-fold) over iNOS. However, due to its peptide nature, this compound is not a desirable drug candidate because it can be metabolized. A hydroxyethylene isostere was proposed as an alternative to the peptide bond to improve bioavailability. A series of eight hydroxyethylene analogues were synthesized and evaluated. Two compounds, N-(4S,9-diamino-6R-hydroxy-nonyl)-nitroguanidine (VI ) and N-(4S,8-diamino-6S-hydroxy-octyl)-nitroguanidine (VII), exhibited exceptional potency, Ki = 0.83 muM and 0.29 muM respectively. The best compound (VII) showed good selectivity for nNOS over eNOS (475-fold) and iNOS (107-fold). The hydroxyethylene isostere proved to be a good surrogate of the peptide bond, and could improve the bioavailability of this class of inhibitors making it a more desirable drug candidate.;The source of the selectivity these inhibitors have for nNOS over eNOS has been observed, but the reasoning for the selectivity over iNOS is unclear. Two dipeptides, D-Phe-D-ArgNO2-NH 2 (1800-fold) and D-Lys-D-Arg NO2-NH2 (1022-fold), showed high selectivity over iNOS. These dipeptides were synthesized and cocrystallized with eNOS and nNOS to compare their binding with iNOS. The altered binding of these D-dipeptides allows the molecules to stretch further from the active site resulting in new inhibitor interactions, which could be the source of their selectivity over iNOS. The understanding of the structural basis for the selectivity could provide better inhibitors. |
