Aminoindoles, a Novel Scaffold with Potent Activity against Plasmodium falciparum
Authors: Barker Robert H. , Urgaonkar Sameer , Mazitschek Ralph , Celatka Cassandra , Skerlj Renato , Cortese Joseph F. , Tyndall Erin , Liu Hanlan , Cromwell Mandy , Sidhu Amar Bir , Guerrero-Bravo Jose E. , Crespo-Llado Keila N. , Serrano Adelfa E. , Lin Jing-wen , Janse Chris J. , Khan Shahid M. , Duraisingh Manoj , Coleman Bradley I. , Angulo-Barturen Inigo , Jiménez-Díaz María Belén , Magán Noemí , Gomez Vanesa , Ferrer Santiago , Martínez María Santos , Wittlin Sergio , Papastogiannidis Petros , O'Shea Thomas , Klinger Jeffrey D. , Bree Mark , Lee Edward , Levine Mikaela , Wiegand Roger C. , Munoz Benito , Wirth Dyann F. , Clardy Jon , Bathurst Ian , Sybertz Edmund 
Published: March 2011

This study characterizes aminoindole molecules that are analogs of Genz-644442. Genz-644442 was identified as a hit in a screen of ∼70,000 compounds in the Broad Institute's small-molecule library and the ICCB-L compound collection at Harvard Medical School. Genz-644442 is a potent inhibitor of
Plasmodium falciparum in vitro
(50% inhibitory concentrations [IC
50
s], 200 to 285 nM) and inhibits
P. berghei in vivo
with an efficacy of >99% in an adapted version of Peters' 4-day suppressive test (W. Peters, Ann. Trop. Med. Parasitol. 69:155–171, 1975). Genz-644442 became the focus of medicinal chemistry optimization; 321 analogs were synthesized and were tested for
in vitro
potency against
P. falciparum
and for
in vitro
absorption, distribution, metabolism, and excretion (ADME) properties. This yielded compounds with IC
50
s of approximately 30 nM. The lead compound, Genz-668764, has been characterized in more detail. It is a single enantiomer with IC
50
s of 28 to 65 nM against
P. falciparum in vitro
. In the 4-day
P. berghei
model, when it was dosed at 100 mg/kg of body weight/day, no parasites were detected on day 4 postinfection. However, parasites recrudesced by day 9. Dosing at 200 mg/kg/day twice a day resulted in cures of 3/5 animals. The compound had comparable activity against
P. falciparum
blood stages in a human-engrafted NOD
-scid
mouse model. Genz-668764 had a terminal half-life of 2.8 h and plasma trough levels of 41 ng/ml when it was dosed twice a day orally at 55 mg/kg/day. Seven-day rat safety studies showed a no-observable-adverse-effect level (NOAEL) at 200 mg/kg/day; the compound was not mutagenic in Ames tests, did not inhibit the hERG channel, and did not have potent activity against a broad panel of receptors and enzymes. Employing allometric scaling and using
in vitro
ADME data, the predicted human minimum efficacious dose of Genz-668764 in a 3-day once-daily dosing regimen was 421 mg/day/70 kg, which would maintain plasma trough levels above the IC
90
against
P. falciparum
for at least 96 h after the last dose. The predicted human therapeutic index was approximately 3, on the basis of the exposure in rats at the NOAEL. We were unable to select for parasites with >2-fold decreased sensitivity to the parent compound, Genz-644442, over 270 days of
in vitro
culture under drug pressure. These characteristics make Genz-668764 a good candidate for preclinical development.