3-Hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylates—A new class of HIV-1 integrase inhibitors Monica Donghi * , Olaf D. Kinzel, Vincenzo Summa Department of Medicinal Chemistry, IRBM, Merck Research Laboratories Rome, Via Pontina km 30,600, 00040 Pomezia, Rome, Italy article info Article history: Received 19 December 2008 Revised 12 February 2009 Accepted 13 February 2009 Available online 20 February 2009 Keywords: HIV-1 integrase Inhibitor Spread assay Pyridopyrimidine Oxalamide abstract A new class of inhibitors of HIV-1 integrase has been optimized to provide selective and highly efficient strand transfer inhibition. Ó 2009 Elsevier Ltd. All rights reserved. The Acquired Immunodeficiency Syndrome (AIDS) is a major epidemic with more than 33 million infected people worldwide. 1 Its etiological agent has been identified as human immunodefi- ciency virus type 1 (HIV-1). Current approved therapies target four steps of the HIV life cycle (fusion, reverse transcription, integration and proteolytic maturation). 2 Triple therapy, com- monly referred to as HAART (highly active antiretroviral therapy) is the standard for HIV treatment. Unfortunately, despite the great efficacy of HAART long term treatment has many side ef- fects and the selection of mutated viruses leads to the failure of the therapy. Therefore there is a continuous need for new agents with improved properties. Integrase is an enzyme encoded by the HIV genome and repre- sents a well established target. It catalyses the insertion and inte- gration of the proviral DNA into the genome of the host cell in two steps: 3 0 -processing (endonucleolytic sequence-specific hydrolysis of the 3 0 -ends of the viral cDNA) and strand transfer (ligation of the viral 3 0 -OH cDNA ends to the phosphate backbone of the host DNA acceptor). 3 While first generation integrase inhibitors attempted to block the whole assembly process, recent series have been designed to specifically inhibit the strand transfer reaction. 4 Selective inhibi- tion of the integrase activity causes an interruption of the HIV-1 replication cycle and represents an answer to the unmet medical need for new improved treatments. 5 Recently the first integrase inhibitor (raltegravir) was approved in the U.S. and in Europe for treatment of HIV infection. 6 In a previous article, we reported the discovery of bicyclic pyrimidinones which were created by linking the N1-Methyl group of the pyrimidinone scaffold 1 7 into a saturated cycle as in 2 (Fig. 1). 8 Herein we describe further studies evolving the 6,7,8,9-tetrahy- dropyrido[1,2-a]pyrimidin-4-one scaffold 2 into a pyrido[1,2- a]pyrimidin-4-one scaffold 3 with the aim of removing the ben- zylic stereocenter. In order to evaluate the validity of the scaffold, the unsubstitut- ed template 4 was first prepared and tested in the enzymatic assay QUICKIN (QI) (Table 1). The compound resulted to be a very potent inhibitor of the strand transfer showing an IC 50 of 22 nM. Efforts were then directed towards the evaluation of different linker atoms like N and C for the substituents at position 9 of the bicyclic scaffold. Amines and amides were tolerated by the enzyme. N-methyl amino derivative 5 lost sixfold compared to the unsubstituted scaf- fold 4 while the N-ethyl amino derivative 6 and the benzamide derivative 8 maintained high activity. The N,N-dimethylamino substituted compound 7 lost threefold. The substitution of 4 with a methyl group in position 9 led to a twofold gain in enzymatic activity (9, IC 50 = 9 nM). In the light of this result we investigated the homologation of amine and amide derivatives. With the introduction of basic substituents (e.g., 10 and 11) a nearly 20-fold loss in intrinsic potency was observed. 0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2009.02.055 * Corresponding author. E-mail address: monica_donghi@merck.com (M. Donghi). Bioorganic & Medicinal Chemistry Letters 19 (2009) 1930–1934 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl