Synthesis, SAR, and biological evaluation of oximino-piperidino-piperidine amides. 1. Orally bioavailable CCR5 receptor antagonists with potent anti-HIV activity

Journal of Medicinal Chemistry

Volumn 45, Issue 14, 2002, Pages 3143-3160

  Palani, Anandan ^a   Shapiro, Sherry ^a   Josien, Hubert ^a   Bara, Thomas ^a   Clader, John W ^a   Greenlee, William J ^a   Cox, Kathleen ^a   Strizki, Julie M ^a   Baroudy, Bahige M ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

4 [(4 BROMOPHENYL)(ETHOXYIMINO)METHYL] 1' [(2,4 DIMETHYL 3 PYRIDINYL)CARBONYL] 4' METHYL 1,4' BIPIPERIDINE; 4 [(4 BROMOPHENYL)(ETHOXYIMINO)METHYL] 1' [(2,4 DIMETHYL 3 PYRIDINYL)CARBONYL] 4' METHYL 1,4' BIPIPERIDINE N OXIDE; AMIDE; ANTIRETROVIRUS AGENT; CHEMOKINE RECEPTOR CCR5; OXIME; PHENYL GROUP; PIPERIDINE DERIVATIVE; RECEPTOR BLOCKING AGENT; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ANTIVIRAL ACTIVITY; ARTICLE; CELL STRAIN 3T3; CHEMICAL MODIFICATION; DRUG BIOAVAILABILITY; DRUG INDICATION; DRUG STRUCTURE; DRUG SYNTHESIS; HUMAN; HUMAN CELL; HUMAN IMMUNODEFICIENCY VIRUS 1; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; MOUSE; NONHUMAN; RAT;

ADMINISTRATION, ORAL; ANIMALS; ANTI-HIV AGENTS; BIOLOGICAL AVAILABILITY; CELL LINE; CYCLIC N-OXIDES; HIV-1; HUMANS; LEUKOCYTES, MONONUCLEAR; MICE; PIPERIDINES; PYRIDINES; RADIOLIGAND ASSAY; RATS; RECEPTORS, CCR5; STRUCTURE-ACTIVITY RELATIONSHIP; VIRUS REPLICATION;

EID: 0037019271     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm0200815     Document Type: Article

References (34)

1. Primary HIV-1 Resistance
2. HIV-1 resistance in newly infected individuals
3. Chemokine receptors: Keys to AIDS pathogenesis?
4. Viral exploitation and subversion of the immune system through chemokine mimicry
5. Chemokine receptors as HIV coreceptors: Targets for therapeutic intervention in AIDS
6. Opportunities for novel therapeutic agents acting at chemokine receptors
7. Identification of RANTES, MIP-1α, and MIP-1β as the major HIV-suppressive factors produced by CD8+ T cells
8. HIV-1 entry inhibitors: Evading the issue
9. Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene
10. Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection
11. The role of viral phenotype and CCR-5 gene defects in HIV-1 transmission and disease progression
12. Novel low molecular weight spirodiketopiperazine derivatives potently inhibit R5 HIV-1 infection through their antagonistic effect on CCR5
13. Small molecule antagonists of chemokine receptors as emerging anti-HIV agents
14. Discovery of novel, potent, and selective small-molecule CCR5 antagonists as anti-IV-1 agents: Synthesis and biological evaluation of anilide derivatives with a quaternary ammonium moiety
15. Antagonists of the human CCR5 receptor as anti-HIV-1 agents. Part 1: Discovery and initial structure-activity relationships for 1-amino-2-phenyl-4-(piperidin-1-yl)butanes
16. Antagonists of the human CCR5 receptor as anti-HIV-1 agents. Part 2: Structure-activity relationships for substituted 2-aryl-1-[n-(methyl)-n-(phenylsulfonyl)amino]-4-(piperidin-1-yl)-butanes
17. 1,3,4-Trisubstituted pyrrolidine CCR5 receptor antagonists. Part 1: Discovery of the pyrrolidine scaffold and determination of its stereochemical requirements
18. 1,3,4-Trisubstituted pyrrolidine CCR5 receptor antagonists. Part 2: Lead optimization affording selective, orally bioavailable compounds with potent anti-HIV activity
19. Discovery of 4-[(Z)-(4-Bromophenyl)(ethoxyimino)methyl]-1′-[(2, 4-dimethyl-3-pyridinyl)carbonyl]-4′-methyl-1,4′-bipiperidine N-oxide (1): An orally bioavailable human CCR5 antagonist for the treatment of HIV infection
20. SCH-C (SCH 351125), an orally bioavailable, small molecule antagonist of the chemokine receptor CCR5, is a potent inhibitor of HIV-1 infection in vitro and in vivo
21. Piperazine-based CCR5 antagonists as HIV-1 inhibitors. II: The discovery of 1-[(2,4-dimethyl-3-pyridinyl)-carbonyl]-4-methyl-4-[3(S)-methyl-4-[1(S) -[4-(trifluoromethyl)-phenyl]ethyl]-1-piperazinyl]piperidine N1-oxide (Sch 350634), an orally bioavailable, potent CCR5 antagonist
22. Enantioselective total synthesis of indolizidine alkaloids 167B and 209D
23. Concise formation of 4-benzyl piperidines and related derivatives using a Suzuki protocol
24. Vpr is required for efficient replication of human immunodeficiency virus type-1 in mononuclear phagocytes
25. Potent, broad spectrum inhibition of human immunodeficiency virus type 1 by the CCR5 monoclonal antibody PRO 140
26. A novel in vivo procedure for the rapid rat pharmacokinetic screening of discovery compounds in rat
27. Piperazine-based CCR5 antagonists as HIV-1 inhibitors. I: 2(S)-methyl piperazine as a key pharmacophore element