210635-18-0Relevant academic research and scientific papers
Stereospecific synthesis, structure-activity relationship, and oral bioavailability of tetrahydropyrimidin-2-one HIV protease inhibitors
De Lucca, George V.,Liang, Jing,De Lucca, Indawati
, p. 135 - 152 (2007/10/03)
The use of tetrahydropyrimidinones as an alternate scaffold for designing HIVPR inhibitors has advantages, over the previously disclosed hexahydro-1,3-diazepin-2-ones, of being more unsymmetrical (different P1/P1'), less crystalline, more soluble, and more lipophilic (mono-ol vs diol). They show a better translation of K(i) to IC90 for the more polar P2 groups that in general give the more potent enzyme inhibitors. Structure- activity relationship (SAR) studies of the tetrahydropyrimidinones showed that the phenylethyl P1' substituent, the hydroxyl group, and the urea carbonyl are all critical for good activity. However, there was significant flexibility in the possible P2/P2' substituents that could be used. Many analogues that contained identical or different P2/P2' substituents, or only one P2 substituent, were found to have excellent enzyme potency and several had excellent antiviral potency. Several of these compounds were examined for oral bioavailability in the rat or the dog at 10 mg/kg. However, the oral bioavailability of the tetrahydropyrimidinones was, in general, less than the corresponding hexahydro-1,3-diazepin-2-ones. Unfortunately, when all factors are considered, including potency, protein binding, solubility, bioavailability, and resistance profile, the tetrahydropyrimidinones did not offer any advantage over the previously disclosed hexahydro-1,3-diazepin-2- ones series.
Stereospecific, Stereoselective Rearrangement of Hexahydro-1,3-diazepin-2-ones to Tetrahydropyrimidin-2-ones and Imidazolidin-2-ones, a Useful Route for the Synthesis of HIV Protease Inhibitors
De Lucca, George V.
, p. 4755 - 4766 (2007/10/03)
We have discovered that hexahydro-5,6-dihydroxy-l,3-diazepin-2-ones can undergo a stereospecific, stereoselective-rearrangement, ring-contraction reaction to give the corresponding tetrahydro-5-hydroxypyrimidin-2-ones. This reaction is very general and proceeds in excellent yields. The rearrangement proceeds through the formation of the aziridinium cationic intermediate I, which is subsequently opened by nucleophilic attack (SN2) at the less hindered carbon to give the rearranged product. The X-ray structure determination of the rearranged product (17a; Figure 1) confirmed the structure and the stereochemical assignments and is consistent with the proposed mechanism. When the urea nitrogens are not substituted, the aziridine product can be isolated, and its structure (24; Figure 2) was also confirmed by X-ray analysis. The aziridine product can be used as a mono N-protecting group to synthesize differentially disubstituted N,N′-dialkylated tetrahydropyrimidin-2-one analogues. The tetrahydro-5-hydroxypyrimidin-2-ones can further undergo a second stereospecific, stereoselective-rearrangement, ring-contraction reaction to give the corresponding imidazolidinones. This second rearrangement is also very general and proceeds in good yields. These tetrahydro-5-hydroxypyrimidin-2-ones and imidazolidinones have previously been shown to be potent HIVPR inhibitors.
Solution-phase synthesis of novel linear oxyamine combinatorial libraries with antibacterial activity
Kung, Pei-Pei,Bharadwaj, Ramesh,Fraser, Allister S.,Cook, Daniel R.,Kawasaki, Andrew M.,Cook, P. Dan
, p. 1846 - 1852 (2007/10/03)
Use of solution phase combinatorial library synthesis led to the discovery of several oxyaminecontaining antibacterial compounds. Solution-phase simultaneous addition of meta-substituted benzyl bromides and 'fix-last' combinatorial strategies were used to prepare libraries. Additional structure-activity relationship studies were conducted by reductive cleavage of the oxyamine moiety and led to loss of antibacterial activity. Several single compounds were designed and synthesized on the basis of library screening results and were shown to have antibacterial activity.
β-lactam derivatives as inhibitors of human cytomegalovirus protease
Yoakim, Christiane,Ogilvie, William W.,Cameron, Dale R.,Chabot, Catherine,Guse, Ingrid,Haché, Bruno,Naud, Julie,O'Meara, Jeff A.,Plante, Raymond,Déziel, Robert
, p. 2882 - 2891 (2007/10/03)
The development of novel monobactam inhibitors of HCMV protease incorporating a carbon side chain at C-4 and a urea function at N-1 is described. Substitution with small groups at the C-3 position of the β- lactam ring gave an increase in enzymatic activity and in stability; however, a lack of selectivity against other serine proteases was noted. The use of both triand tetrasubstituted urea functionalities gave effective inhibitors of HCMV protease. Benzyl substitution of the urea moiety was beneficial, especially when strong electron-withdrawing groups where attached at the para position. Modest antiviral activity was found in a plaque reduction assay.
