piperidines and vicriviroc

Human immunodeficiency virus (HIV) is a retrovirus that is the causative agent of acquired immunodeficiency syndrome (AIDS). Current HIV therapy is based on targeting two critical enzymes in the viral replication machinery: reverse transcriptase and a virally encoded protease. Although mortality rates due to HIV infection have been dramatically reduced, AIDS remains a major health problem throughout the world. The emergence of HIV variants that are resistant to current therapies and potential toxicity associated with their chronic use has highlighted the need for new approaches to HIV inhibition. Identification of the mechanisms underlying viral entry into the host cell has provided a number of novel therapeutic targets and the first of these HIV fusion inhibitors (enfuvirtide [pentafuside, T-20, Fuzeon; Roche Laboratories and Trimeris]) has recently been approved in the US and Europe. This review will focus on recent progress in the development of therapeutics that target the HIV entry process.

Topics: Amino Acid Motifs; Animals; Anti-HIV Agents; CCR5 Receptor Antagonists; CD4 Antigens; Clinical Trials as Topic; Cyclic N-Oxides; Dogs; Drug Design; Drug Evaluation, Preclinical; Drug Resistance, Viral; Drug Therapy, Combination; Enfuvirtide; Haplorhini; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Membrane Fusion; Membrane Glycoproteins; Organic Chemicals; Oximes; Peptide Fragments; Piperazines; Piperidines; Protein Binding; Pyridines; Pyrimidines; Rabbits; Receptors, CCR5; Receptors, CXCR4; Reverse Transcriptase Inhibitors; Spiro Compounds

In addition to being an important receptor in leukocyte activation and mobilization, CCR5 is the essential coreceptor for human immunodeficiency virus (HIV). A large number of small-molecule CCR5 antagonists have been reported that show potent activities in blocking chemokine function and HIV entry. To facilitate the design and development of next generation CCR5 antagonists, docking models for major classes of CCR5 antagonists were created by using site-directed mutagenesis and CCR5 homology modeling. Five clinical candidates: maraviroc, vicriviroc, aplaviroc, TAK-779, and TAK-220 were used to establish the nature of the binding pocket in CCR5. Although the five antagonists are very different in structure, shape, and electrostatic potential, they were able to fit in the same binding pocket formed by the transmembrane (TM) domains of CCR5. It is noteworthy that each antagonist displayed a unique interaction profile with amino acids lining the pocket. Except for TAK-779, all antagonists showed strong interaction with Glu283 in TM 7 via their central basic nitrogen. The fully mapped binding pocket of CCR5 is being used for structure-based design and lead optimization of novel anti-HIV CCR5 inhibitors with improved potency and better resistance profile.

Topics: Amides; Amino Acid Sequence; Animals; Anti-HIV Agents; Benzoates; Binding Sites; CCR5 Receptor Antagonists; CHO Cells; Cricetinae; Cricetulus; Cyclohexanes; Diketopiperazines; HIV Fusion Inhibitors; HIV-1; Humans; Hydrophobic and Hydrophilic Interactions; Inhibitory Concentration 50; Maraviroc; Membrane Fusion; Models, Molecular; Molecular Sequence Data; Molecular Structure; Mutagenesis, Site-Directed; Piperazines; Piperidines; Protein Structure, Secondary; Protein Structure, Tertiary; Pyrimidines; Quaternary Ammonium Compounds; Radioligand Assay; Receptors, CCR5; Sequence Homology, Amino Acid; Spiro Compounds; Static Electricity; Transfection; Triazoles

The nature and the size of the benzylic substituent are shown to be the key to controlling receptor selectivity (CCR5 vs M1, M2) and potency in the title compounds. Optimization of the lead benzylic methyl compound 3 led to the methoxymethyl analogue 30, which had excellent receptor selectivity and oral bioavailability in rats and monkeys. Compound 30 (Sch-417690/Sch-D), a potent inhibitor of HIV-1 entry into target cells, is currently in clinical trials.

Topics: Administration, Oral; Animals; Anti-HIV Agents; Biological Availability; Brain; Cation Transport Proteins; CCR5 Receptor Antagonists; Digestive System; Ether-A-Go-Go Potassium Channels; HIV-1; Humans; In Vitro Techniques; Leukocytes, Mononuclear; Macaca fascicularis; Piperazines; Piperidines; Potassium Channels; Potassium Channels, Voltage-Gated; Pyrimidines; Rats; Stereoisomerism; Structure-Activity Relationship