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

Abstract

We previously reported the discovery of 4-[(Z)-(4-bromophenyl)(ethoxyimino)methyl]-1'-[(2,4-dimethyl-3-pyridinyl)carbonyl]-4'-methyl-1,4'-bipiperidine N-oxide 1 (SCH 351125) as an orally bioavailable human CCR5 antagonist for the treatment of HIV-1 infection. Herein, we describe in detail the discovery of 1 from our initial lead compound as well as the synthesis and SAR studies directed toward optimization of substitution at the phenyl, oxime, and right-hand side amide groups in the oximino-piperidino-piperidine series. Substitutions (4-Br, 4-CF(3), 4-OCF(3), 4-SO(2)Me, and 4-Cl) at the phenyl group are well-tolerated, and small alkyl substitutions (Me, Et, (n)()Pr, (i)()Pr, and cyclopropyl methyl) at the oxime moiety are preferred for CCR5 antagonism. The 2,6-dimethylnicotinamide N-oxide moiety is the optimal choice for the right-hand side. Several compounds in this series, including compound 1, exhibited excellent antiviral activity in vitro. Compound 1, which has a favorable pharmacokinetic profile in rodents and primates, excellent oral bioavailability, and potent antiviral activity against a wide range of primary HIV-1 isolates, is a potentially promising new candidate for treatment of HIV-1 infection.

• Authors: Anandan Palani, Sherry Shapiro, Hubert Josien, Thomas Bara, John W Clader, William J Greenlee, Kathleen Cox, Julie M Strizki, Bahige M Baroudy
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 45 Issue 14 Pg. 3143-60 (Jul 04 2002) ISSN: 0022-2623 [Print] United States
• PMID: 12086500 (Publication Type: Journal Article)

Chemical References

• Anti-HIV Agents
• CCR5 Receptor Antagonists
• Cyclic N-Oxides
• Oximes
• Piperidines
• Pyridines
• Ancriviroc

Topics

• Administration, Oral
• Animals
• Anti-HIV Agents (chemical synthesis, chemistry, pharmacology)
• Biological Availability
• CCR5 Receptor Antagonists
• Cell Line
• Cyclic N-Oxides (chemical synthesis, chemistry, pharmacology)
• HIV-1 (drug effects, isolation & purification)
• Humans
• In Vitro Techniques
• Leukocytes, Mononuclear (drug effects, virology)
• Mice
• Oximes
• Piperidines (chemical synthesis, chemistry, pharmacology)
• Pyridines (chemical synthesis, chemistry, pharmacology)
• Radioligand Assay
• Rats
• Structure-Activity Relationship
• Virus Replication (drug effects)