title: Discovery of tetrahydropyrazolopyrimidine carboxamide derivatives as potent and orally active antitubercular agents.
abstract: Tetrahydropyrazolo[1,5-a]pyrimidine scaffold was identified as a hit series from a Mycobacterium tuberculosis (Mtb) whole cell high through-put screening (HTS) campaign. A series of derivatives of this class were synthesized to evaluate their structure-activity relationship (SAR) and structure-property relationship (SPR). Compound 9 had a promising in vivo DMPK profile in mouse and exhibited potent in vivo activity in a mouse efficacy model, achieving a reduction of 3.5 log CFU of Mtb after oral administration to infected mice once a day at 100 mg/kg for 28 days. Thus, compound 9 is a potential candidate for inclusion in combination therapies for both drug-sensitive and drug-resistant TB.
authors.affiliation: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, 138670 Singapore.
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Yokokawa
authors.affiliation: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, 138670 Singapore.
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
authors.affiliation: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, 138670 Singapore.
authors.forename: Wai Ling
authors.initials: WL
authors.lastname: Chan
authors.affiliation: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, 138670 Singapore.
authors.forename: Shi Hua
authors.initials: SH
authors.lastname: Ang
authors.affiliation: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, 138670 Singapore.
authors.forename: Josephine
authors.initials: J
authors.lastname: Wong
authors.affiliation: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, 138670 Singapore.
authors.forename: Ida
authors.initials: I
authors.lastname: Ma
authors.affiliation: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, 138670 Singapore.
authors.forename: Srinivasa P S
authors.initials: SP
authors.lastname: Rao
authors.affiliation: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, 138670 Singapore.
authors.forename: Ujjini
authors.initials: U
authors.lastname: Manjunatha
authors.affiliation: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, 138670 Singapore.
authors.forename: Suresh B
authors.initials: SB
authors.lastname: Lakshminarayana
authors.affiliation: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, 138670 Singapore.
authors.forename: Maxime
authors.initials: M
authors.lastname: Herve
authors.affiliation: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, 138670 Singapore.
authors.forename: Cyrille
authors.initials: C
authors.lastname: Kounde
authors.affiliation: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, 138670 Singapore.
authors.forename: Bee Huat
authors.initials: BH
authors.lastname: Tan
authors.affiliation: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, 138670 Singapore.
authors.forename: Pamela
authors.initials: P
authors.lastname: Thayalan
authors.affiliation: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, 138670 Singapore.
authors.forename: Seow Hwee
authors.initials: SH
authors.lastname: Ng
authors.affiliation: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, 138670 Singapore.
authors.forename: Mahesh
authors.initials: M
authors.lastname: Nanjundappa
authors.affiliation: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, 138670 Singapore.
authors.forename: Sindhu
authors.initials: S
authors.lastname: Ravindran
authors.affiliation: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, 138670 Singapore.
authors.forename: Peck
authors.initials: P
authors.lastname: Gee
authors.affiliation: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, 138670 Singapore.
authors.forename: Maria
authors.initials: M
authors.lastname: Tan
authors.affiliation: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, 138670 Singapore.
authors.forename: Liu
authors.initials: L
authors.lastname: Wei
authors.affiliation: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, 138670 Singapore.
authors.forename: Anne
authors.initials: A
authors.lastname: Goh
authors.affiliation: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, 138670 Singapore.
authors.forename: Pei-Yu
authors.initials: PY
authors.lastname: Chen
authors.affiliation: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, 138670 Singapore.
authors.forename: Kok Sin
authors.initials: KS
authors.lastname: Lee
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John J. Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Chen
authors.initials: C
authors.lastname: Zhong
authors.affiliation: Novartis Institute for Biomedical Research , Basel CH-4056, Switzerland.
authors.forename: Trixie
authors.initials: T
authors.lastname: Wagner
authors.affiliation: Novartis Institute for Biomedical Research , Basel CH-4056, Switzerland.
authors.forename: Ina
authors.initials: I
authors.lastname: Dix
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John J. Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Arnab K
authors.initials: AK
authors.lastname: Chatterjee
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John J. Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Kevin
authors.initials: K
authors.lastname: Pethe
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John J. Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Kelli
authors.initials: K
authors.lastname: Kuhen
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John J. Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Richard
authors.initials: R
authors.lastname: Glynne
authors.affiliation: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, 138670 Singapore.
authors.forename: Paul
authors.initials: P
authors.lastname: Smith
authors.affiliation: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, 138670 Singapore.
authors.forename: Pablo
authors.initials: P
authors.lastname: Bifani
authors.affiliation: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, 138670 Singapore.
authors.forename: Jan
authors.initials: J
authors.lastname: Jiricek
keywords: Antituberculosis; structure−activity relationship; structure−property relationship; tetrahydropyrazolo[1,5-a]pyrimidine