2,3-Diaminopyrazines as rho kinase inhibitors

Preclinical pharmacology, ocular tolerability and ocular hypotensive efficacy of a novel non-peptide bradykinin mimetic small molecule

“…Steroids raise IOP in mice, rats, cats, cattle and humans (see Gerometta et al, 2004 and references therein) but not reliably and consistently in rabbits (Knepper et al, 1985;Gelatt et al, 1998) or monkeys (Fingert et al, 2001). However, other classes of agents like rho kinase inhibitors (Henderson et al, 2010), carbonic anhydrase inhibitors (Desantis, 2000), beta-blockers (Gupta et al, 2007) and DP-receptor and EP 2 -receptor agonist PGs -190997 (i.e. from beginning of the study for each respective concentration).…”

“…However, due an inherent 15% variability amongst the data sets for these various assays, only inhibitions of binding caused by test agents that are >50% are considered relevant (bolded items in the Table above). monkey colony had been sufficiently elevated to permit testing of numerous classes of pharmacological agents over the years (Desantis, 2000;Hellberg et al, 2002;May et al, 2003;Sharif et al, 2009;Henderson et al, 2010) and the IOPs had remained stable for many years. Thus, following a baseline IOP measurement, test compounds made in a suitable sterile vehicle (Maxidex vehicle: 0.5% hydroxyl propyl methyl cellulose (suspending agent); 0.05% polysorbate 80 (a nonionic surfactant that wets the suspended particles); 0.2% dibasic sodium phosphate buffer (buffering agent); 0.75% NaCl (tonicity agent); 0.01% disodium edetate dihydrate (preservative aid); 0.01% benzalkonium chloride (preservative); pH adjusted to 6e7.4 using NaOH and/or HCl; 100% purified water) were instilled in the OHT right eyes only of eight to ten conscious cynomolgus monkeys.…”

Discovery of novel inhibitors for the treatment of glaucoma

“…This novel derivative significantly reduced IOP in ocular hypertensive monkeys after one hour dosing and the effect was sustained for six hours in the hypertensive eye [77]. Similarly, in 2010 Henderson et al, identified 2,3-diaminopyrazines as ROCK specific inhibitors [78]. The structure activity relationship for the two hit compounds led to the discovery of a series of other compounds.…”

“…Some of these compounds demonstrated less than 500 nM and 100 nM activity for ROCK1 and ROCK2, respectively. Further, these compounds were studied in vivo in rabbits and monkeys, where one of the compounds exhibited higher IOP lowering effect [78]. In 2011, Ray et al, identified thrombin/FactorXa building block as a ROCK1 inhibitor by fragment based NMR screening with the aid of small literature focused library [79].…”

General method for nucleophilic aromatic substitution of aryl fluorides and chlorides with dimethylamine using hydroxide-assisted decomposition of N,N-dimethylforamide

“…[11] Additionally, numerous aromatic natural products are substituted with a dimethylamino group with some notable examples being Tigecycline, [2] Minocycline, [12] Orthoformimycin, [13] and Dendrodione. [14] While installation of the dimethylamino group can be carried out by nucleophilic aromatic substitution (S N Ar), the dimethylamine nucleophile often requires high temperatures and reaction times [15–17] to install, which can be challenging when using premade solutions given dimethylamine’s volatility.…”