Pharmacokinetically-guided lead optimization of nitrofuranylamide anti-tuberculosis agents

Nageshwar R. Budha, Nitin Mehrotra, Rajendra Tangallapally, Tangallapally Rakesh, Jianjun Qi, Antwan J. Daniels, Richard E. Lee, Bernd Meibohm

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

In an effort to develop novel and more potent therapies to treat tuberculosis, a new class of chemical agents, nitrofuranylamides, is being developed. The present study examines biopharmaceutic properties and preclinical pharmacokinetics of nitrofuranylamides at early stages of drug discovery to accelerate the optimization of leads into development candidates. The first tested compound, Lee 562, had high anti-tuberculosis activity in vitro, but exhibited poor metabolic stability resulting in a high systemic clearance, a short elimination half-life and low oral bioavailability in vivo in rats. Thus, two follow-up compounds were designed and tested that included structural modifications for increased metabolic stability. Both compounds showed improved metabolic stability compared to Lee 562, with Lee 878 being much more stable than Lee 952. As a consequence, the oral bioavailability of Lee 878 reached ∼27% compared to 16% for the other two compounds. This observation prompted us to select compounds based on metabolic stability screening and a new set of nine compounds with high in vitro activity were tested for metabolic stability. The most stable compound in the assay, Lee 1106 was selected for further pharmacokinetic evaluation in rats. Surprisingly, Lee 1106 exhibited poor oral bioavailability, 4.6%. Biopharmaceutic evaluation of the compound showed that the compound has poor aqueous solubility and a high clog P. Based on these results, a screening paradigm was developed for optimization of the nitrofuranylamide lead compounds in a timely and cost-effective manner that might also be applicable to other classes of anti-infective drugs.

Original languageEnglish (US)
Pages (from-to)157-165
Number of pages9
JournalAAPS Journal
Volume10
Issue number1
DOIs
StatePublished - Mar 14 2008

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Biopharmaceutics
Biological Availability
Tuberculosis
Pharmacokinetics
Drug Discovery
Solubility
Half-Life
Costs and Cost Analysis
Pharmaceutical Preparations
Lead
In Vitro Techniques
Therapeutics

All Science Journal Classification (ASJC) codes

  • Pharmaceutical Science

Cite this

Budha, N. R., Mehrotra, N., Tangallapally, R., Rakesh, T., Qi, J., Daniels, A. J., ... Meibohm, B. (2008). Pharmacokinetically-guided lead optimization of nitrofuranylamide anti-tuberculosis agents. AAPS Journal, 10(1), 157-165. https://doi.org/10.1208/s12248-008-9017-8

Pharmacokinetically-guided lead optimization of nitrofuranylamide anti-tuberculosis agents. / Budha, Nageshwar R.; Mehrotra, Nitin; Tangallapally, Rajendra; Rakesh, Tangallapally; Qi, Jianjun; Daniels, Antwan J.; Lee, Richard E.; Meibohm, Bernd.

In: AAPS Journal, Vol. 10, No. 1, 14.03.2008, p. 157-165.

Research output: Contribution to journalArticle

Budha, NR, Mehrotra, N, Tangallapally, R, Rakesh, T, Qi, J, Daniels, AJ, Lee, RE & Meibohm, B 2008, 'Pharmacokinetically-guided lead optimization of nitrofuranylamide anti-tuberculosis agents', AAPS Journal, vol. 10, no. 1, pp. 157-165. https://doi.org/10.1208/s12248-008-9017-8
Budha NR, Mehrotra N, Tangallapally R, Rakesh T, Qi J, Daniels AJ et al. Pharmacokinetically-guided lead optimization of nitrofuranylamide anti-tuberculosis agents. AAPS Journal. 2008 Mar 14;10(1):157-165. https://doi.org/10.1208/s12248-008-9017-8
Budha, Nageshwar R. ; Mehrotra, Nitin ; Tangallapally, Rajendra ; Rakesh, Tangallapally ; Qi, Jianjun ; Daniels, Antwan J. ; Lee, Richard E. ; Meibohm, Bernd. / Pharmacokinetically-guided lead optimization of nitrofuranylamide anti-tuberculosis agents. In: AAPS Journal. 2008 ; Vol. 10, No. 1. pp. 157-165.
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