title: Novel Amino-pyrazole Ureas with Potent In Vitro and In Vivo Antileishmanial Activity.
abstract: Visceral leishmaniasis is a severe parasitic disease that is one of the most neglected tropical diseases. Treatment options are limited, and there is an urgent need for new therapeutic agents. Following an HTS campaign and hit optimization, a novel series of amino-pyrazole ureas has been identified with potent in vitro antileishmanial activity. Furthermore, compound 26 shows high levels of in vivo efficacy (>90%) against Leishmania infantum, thus demonstrating proof of concept for this series.
authors.affiliation: Drugs for Neglected Diseases initiative (DNDi) , 15 Chemin Louis-Dunant, 1202 Geneva, Switzerland.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Mowbray
authors.affiliation: Drugs for Neglected Diseases initiative (DNDi) , 15 Chemin Louis-Dunant, 1202 Geneva, Switzerland.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Braillard
authors.affiliation: Drugs for Neglected Diseases initiative (DNDi) , 15 Chemin Louis-Dunant, 1202 Geneva, Switzerland.
authors.forename: William
authors.initials: W
authors.lastname: Speed
authors.affiliation: Sandexis Medicinal Chemistry Ltd., Innovation House , Discovery Park, Ramsgate Road, Sandwich, Kent CT13 9ND, United Kingdom.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Glossop
authors.affiliation: Sandexis Medicinal Chemistry Ltd., Innovation House , Discovery Park, Ramsgate Road, Sandwich, Kent CT13 9ND, United Kingdom.
authors.forename: Gavin A
authors.initials: GA
authors.lastname: Whitlock
authors.affiliation: Sandexis Medicinal Chemistry Ltd., Innovation House , Discovery Park, Ramsgate Road, Sandwich, Kent CT13 9ND, United Kingdom.
authors.forename: Karl R
authors.initials: KR
authors.lastname: Gibson
authors.affiliation: Sandexis Medicinal Chemistry Ltd., Innovation House , Discovery Park, Ramsgate Road, Sandwich, Kent CT13 9ND, United Kingdom.
authors.forename: James E J
authors.initials: JE
authors.lastname: Mills
authors.affiliation: Pfizer Worldwide Medicinal Chemistry , The Portway Building, Granta Park, Great Abington, Cambridge CB21 6GS, United Kingdom.
authors.forename: Alan D
authors.initials: AD
authors.lastname: Brown
authors.affiliation: AMG Consultants Ltd., Discovery Park House , Discovery Park, Ramsgate Road, Sandwich, Kent CT13 9ND, United Kingdom.
authors.forename: J Mark F
authors.initials: JM
authors.lastname: Gardner
authors.affiliation: WuXi AppTec (Wuhan) Company Ltd. , 666 Gaoxin Road, East Lake High-Tech Development Zone, Wuhan 430075, People's Republic of China.
authors.forename: Yafeng
authors.initials: Y
authors.lastname: Cao
authors.affiliation: WuXi AppTec (Wuhan) Company Ltd. , 666 Gaoxin Road, East Lake High-Tech Development Zone, Wuhan 430075, People's Republic of China.
authors.forename: Wen
authors.initials: W
authors.lastname: Hua
authors.affiliation: iThemba Pharmaceuticals , Building T5, Pinelands Site, High Street, Modderfontein 1609, Gauteng, South Africa.
authors.forename: Garreth L
authors.initials: GL
authors.lastname: Morgans
authors.affiliation: Laboratory for Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp , S7, Universiteitsplein 1, 2610 Wilrijk, Antwerp, Belgium.
authors.forename: Pim-Bart
authors.initials: PB
authors.lastname: Feijens
authors.affiliation: Laboratory for Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp , S7, Universiteitsplein 1, 2610 Wilrijk, Antwerp, Belgium.
authors.forename: An
authors.initials: A
authors.lastname: Matheeussen
authors.affiliation: Laboratory for Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp , S7, Universiteitsplein 1, 2610 Wilrijk, Antwerp, Belgium.
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Maes
mesh_terms: D000818:Animals; D000977:Antiparasitic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D006224:Cricetinae; D005260:Female; D006801:Humans; D007893:Leishmania donovani / Q000187:drug effects*; D018314:Leishmania infantum / Q000187:drug effects*; D007898:Leishmaniasis, Visceral / Q000188:drug therapy; D008647:Mesocricetus; D008861:Microsomes / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: C000607193:4-(4-fluorophenyl)-N-(3-(pyridin-2-yl)-1H-pyrazol-5-yl)piperazine-1-carboxamide; D000977:Antiparasitic Agents; D011720:Pyrazoles; D014508:Urea