Can We Make Small Molecules Lean? Optimization of a Highly Lipophilic TarO Inhibitor.

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Title: Can We Make Small Molecules Lean? Optimization of a Highly Lipophilic TarO Inhibitor.
Authors: Mandal M; Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States., Tan Z; Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States., Madsen-Duggan C; Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States., Buevich AV; Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States., Caldwell JP; Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States., Dejesus R; Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States., Flattery A; Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States., Garlisi CG; Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States., Gill C; Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States., Ha SN; Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States., Ho G; Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States., Koseoglu S; Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States., Labroli M; Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States., Basu K; Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States., Lee SH; Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States., Liang L; Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States., Liu J; Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States., Mayhood T; Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States., McGuinness D; Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States., McLaren DG; Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States., Wen X; Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States., Parmee E; Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States., Rindgen D; Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States., Roemer T; Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States., Sheth P; Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States., Tawa P; Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States., Tata J; Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States., Yang C; Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States., Yang SW; Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States., Xiao L; Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States., Wang H; Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States., Tan C; Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States., Tang H; Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States., Walsh P; Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States., Walsh E; Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States., Wu J; Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States., Su J; Global Chemistry, ‡Early Discovery Bacteriology, §Discovery Pharmaceutical Sciences, ∥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ⊥In Vivo Pharmacology, and #In Vitro Pharmacology, MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States.
Source: Journal of medicinal chemistry [J Med Chem] 2017 May 11; Vol. 60 (9), pp. 3851-3865. Date of Electronic Publication: 2017 Mar 29.
Publication Type: Journal Article
Journal Info: Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE
Database: MEDLINE Ultimate
Description
ISSN:1520-4804
DOI:10.1021/acs.jmedchem.7b00113