Discovery and Synthesis of HIV Integrase Inhibitors:  Development of Potent and Orally Bioavailable N-Methyl Pyrimidones

Abstract

The human immunodeficiency virus type-1 (HIV-1) encodes three enzymes essential for viral replication: a reverse transcriptase, a protease, and an integrase. The latter is responsible for the integration of the viral genome into the human genome and, therefore, represents an attractive target for chemotherapeutic intervention against AIDS. A drug based on this mechanism has not yet been approved. Benzyl-dihydroxypyrimidine-carboxamides were discovered in our laboratories as a novel and metabolically stable class of agents that exhibits potent inhibition of the HIV integrase strand transfer step. Further efforts led to very potent compounds based on the structurally related N-Me pyrimidone scaffold. One of the more interesting compounds in this series is the 2-N-Me-morpholino derivative 27a, which shows a CIC95 of 65 nM in the cell in the presence of serum. The compound has favorable pharmacokinetic properties in three preclinical species and shows no liabilities in several counterscreening assays.

Pharmacophore modelling and atom-based 3D-QSAR studies on N-methyl pyrimidones as HIV-1 integrase inhibitors

“…For this study, 49 compounds of N-methyl pyrimidones 22 and raltegravir 23 having experimental activities are used to predict theoretical activity are shown in Tables 1 and 2. The biological activity data was reported in the form of IC 50 .…”

HIV-1 integrase inhibitors: 2007-2008 update

“…Among the several active N-methyl pyrimidones, compounds 132-139 showed potent inhibitory activity in both enzymatic and cell-based assays. 67 Methyl substitution on position 4 in the pyrrolidine ring resulted in the most potent IN inhibition (IC 50 5 0.01 mM), but poor antiviral activity in a cell-based assay (CIC 95 41 mM), replacing methyl by hydroxyl improved cell-based activity (132) with a CIC 95 value of 0.63 mM. Methoxy (133) or fluorine (134) substitution in place of hydroxyl improved both enzymatic and cell-based inhibitory activity.…”

Oximes of six-membered heterocyclic compounds with two and three heteroatoms. II.* Reactions and biological activity (review)

“…Cyclization of the O-methyl oxime of hexa-2,4-dienal (20) in the presence of a chiral chloronitroso dienophile in chloroform followed by oxidation (with OsO 4 ) gives the 1,2-oxazine O-methyloxime 21 [38,39]. The addition of dimethyl acetylenedicarboxylate to derivatives of morpholine or 1,4-thiazine oximes 24 gives the oxime ethers 25 as the only products [42] O-Acetyl derivatives of morpholine oximes were obtained in the oxime/acyl chloride/ethyl acetate system or in chloroform [43,44].…”

“…In boiling toluene in the presence of CoCl 2 the quinoxaline oxime 98 gives the tetrazine 99 [118]. In boiling xylene the morpholine oxime ether 25 forms the pyrimidine derivative 100 with a yield of 54% [42].…”