Discovery of a potent and selective ROMK inhibitor with improved pharmacokinetic properties based on an octahydropyrazino[2,1-c][1,4]oxazine scaffold

Discovery of Small Molecule Renal Outer Medullary Potassium (ROMK) Channel Inhibitors: A Brief History of Medicinal Chemistry Approaches To Develop Novel Diuretic Therapeutics

“…The Merck team also published multiple patents reporting the synthesis and evaluation of a novel class of fused, bicyclic piperazine based inhibitors, 11 – 16 (Figure ). − These fused bicyclic piperazine scaffolds would reduce basicity, based on calculated p K a , and increase rigidity of the compounds . This steric and electronic modulation was theorized to result in compounds being less susceptible to oxidative metabolism.…”

“…Replacement of phthalide functional group with previously established pharmacophores resulted in several different analogs. Two of these analogs, 14 and 15 , had improved ROMK selectivity over hERG when compared to ( R , S )- 13 , with 14 having the best ROMK selectivity of the series, 75.9-fold selectivity for ROMK over hERG. The second analog series, the 2-methylbenzonitrile, e.g., 15 , was explored with the addition of a fluorine and inclusion of various heteroaromatic ring linkers between the acetamide and tetrazole groups.…”

“…28−31 These fused bicyclic piperazine scaffolds would reduce basicity, based on calculated pK a , and increase rigidity of the compounds. 32 This steric and electronic modulation was theorized to result in compounds being less susceptible to oxidative metabolism. 7).…”

“…The in vivo PK profile of 16 was evaluated across preclinical species and was found to be consistent with oral QD dosing (Table 5). 32 In a parallel approach, Walsh and co-workers at Merck Research Laboratories reported the development of a piperazinyl diol series with superior potency, selectivity, and PK properties as ROMK inhibitors. 33 Following the SAR studies on their previously reported 7, they replaced the righthand nitro group with a 3-methoxy-4-cyanophenyl moiety, generating 17, a similarly potent ROMK inhibitor and with a promising 18-fold selectivity over hERG (Figure 8).…”

In Silico Studies of N-(Phenyl Substituted) 2-([Phenyl Substituted) Methylidene] Amino)-N,4- Diphenyl-6h-1,3-Oxazin-6-Amine Derivatives as Potential Antibacterial Agents

“…During the past years considerable evidence have also accumulated to demonstrate the efficacy of 1,3-oxazines including antibacterial 1,2,3,4 , antitubercular 5,6,7 , anticancer 8,9 , anticoagulant 10,11 and anti-HIV activity 12,13 . Literature survey revealed that slight modification in the structure can cause wide variations in activity, which prompted us to undertake the synthesis of various Schiff bases of oxazine derivatives with the aim of having improved activity, lesser toxicity.…”