title: Comprehensive physicochemical, pharmacokinetic and activity profiling of anti-TB agents.
abstract: OBJECTIVE
  The discovery and development of TB drugs has met limited success, with two new drugs approved over the last 40 years. Part of the difficulty resides in the lack of well-established in vitro or in vivo targets of potency and physicochemical and pharmacokinetic parameters. In an attempt to benchmark and compare such properties for anti-TB agents, we have experimentally determined and compiled these parameters for 36 anti-TB compounds, using standardized and centralized assays, thus ensuring direct comparability across drugs and drug classes.
  
  
  METHODS
  Potency parameters included growth inhibition, cidal activity against growing and non-growing bacteria and activity against intracellular mycobacteria. Pharmacokinetic parameters included basic physicochemical properties, solubility, permeability and metabolic stability. We then attempted to establish correlations between physicochemical, in vitro and in vivo pharmacokinetic and pharmacodynamic indices to tentatively inform future drug discovery efforts.
  
  
  RESULTS
  Two-thirds of the compounds tested showed bactericidal and intramacrophage activity. Most compounds exhibited favourable solubility, permeability and metabolic stability in standard in vitro pharmacokinetic assays. An analysis of human pharmacokinetic parameters revealed associations between lipophilicity and volume of distribution, clearance, plasma protein binding and oral bioavailability. Not surprisingly, most compounds with favourable pharmacokinetic properties complied with Lipinski's rule of five.
  
  
  CONCLUSIONS
  However, most attempts to detect in vitro-in vivo correlations were unsuccessful, emphasizing the challenges of anti-TB drug discovery. The objective of this work is to provide a reference dataset for the TB drug discovery community with a focus on comparative in vitro potency and pharmacokinetics.
authors.affiliation: Novartis Institute for Tropical Diseases, Singapore.
authors.forename: Suresh B
authors.initials: SB
authors.lastname: Lakshminarayana
authors.affiliation: Novartis Institute for Tropical Diseases, Singapore.
authors.forename: Tan Bee
authors.initials: TB
authors.lastname: Huat
authors.affiliation: Department of Pharmacy, National University of Singapore, Singapore.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Ho
authors.affiliation: Novartis Institute for Tropical Diseases, Singapore.
authors.forename: Ujjini H
authors.initials: UH
authors.lastname: Manjunatha
authors.affiliation: Novartis Institute for Tropical Diseases, Singapore veronique.dartois@rutgers.edu.
authors.forename: Véronique
authors.initials: V
authors.lastname: Dartois
authors.affiliation: Novartis Institute for Tropical Diseases, Singapore Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Thomas
authors.initials: T
authors.lastname: Dick
authors.affiliation: Novartis Institute for Tropical Diseases, Singapore.
authors.forename: Srinivasa P S
authors.initials: SP
authors.lastname: Rao
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D002460:Cell Line; D055598:Chemical Phenomena; D004355:Drug Stability; D008264:Macrophages / Q000382:microbiology; D051379:Mice; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D010539:Permeability; D012995:Solubility
chemical_list: D000995:Antitubercular Agents
keywords: Mycobacterium tuberculosis; in vitro potency; pharmacodynamics