Tricyclic HIV integrase inhibitors: VI. SAR studies of 'benzyl flipped' C3-substituted pyrroloquinolines

Sammy Metobo; Michael Mish; Haolun Jin; Salman Jabri; Rachael Lansdown; Xiaowu Chen; Manuel Tsiang; Matthew Wright; Choung U Kim

doi:10.1016/j.bmcl.2008.12.079

Tricyclic HIV integrase inhibitors: VI. SAR studies of 'benzyl flipped' C3-substituted pyrroloquinolines

Bioorg Med Chem Lett. 2009 Feb 15;19(4):1187-90. doi: 10.1016/j.bmcl.2008.12.079. Epub 2008 Dec 25.

Authors

Sammy Metobo¹, Michael Mish, Haolun Jin, Salman Jabri, Rachael Lansdown, Xiaowu Chen, Manuel Tsiang, Matthew Wright, Choung U Kim

Affiliation

¹ Gilead Sciences, Medicinal Chemistry, Inc. 333 Lakeside Drive, Foster City, CA 94404, USA.

PMID: 19167883
DOI: 10.1016/j.bmcl.2008.12.079

Abstract

A series of C3 halobenzyl-substituted tricyclic HIV integrase inhibitors was prepared. Improvement in cell-based inhibitor potency was observed in comparison to previously disclosed tricyclic pyrroloquinolines carrying the 'halobenzyl tail' at the lactam nitrogen. Animal PK for several of the C3-substituted inhibitors was examined, with a dihaloaryl analog achieving good balance in protein-shifted EC(50) and t(1/2) in animal PK studies.

MeSH terms

Administration, Oral
Animals
Anti-HIV Agents / chemical synthesis*
Anti-HIV Agents / chemistry
Anti-HIV Agents / pharmacology*
Dogs
Drug Design
HIV Integrase Inhibitors / chemical synthesis*
HIV Integrase Inhibitors / chemistry
HIV Integrase Inhibitors / pharmacology*
Humans
Molecular Structure
Pyrroles / chemical synthesis*
Pyrroles / chemistry
Pyrroles / pharmacology*
Quinolines / chemical synthesis*
Quinolines / chemistry
Quinolines / pharmacology*
Rats
Structure-Activity Relationship

Substances

Anti-HIV Agents
HIV Integrase Inhibitors
Pyrroles
Quinolines
pyrroloquinoline