1330596-01-4Relevant academic research and scientific papers
Substituted imidazopyridazines are potent and selective inhibitors of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1)
Chapman, Timothy M.,Osborne, Simon A.,Bouloc, Nathalie,Large, Jonathan M.,Wallace, Claire,Birchall, Kristian,Ansell, Keith H.,Jones, Hayley M.,Taylor, Debra,Clough, Barbara,Green, Judith L.,Holder, Anthony A.
, p. 3064 - 3069 (2013/06/26)
A series of imidazopyridazines which are potent inhibitors of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1) was identified from a high-throughput screen against the isolated enzyme. Subsequent exploration of the SAR and optimisation has yielded leading members which show promising in vitro anti-parasite activity along with good in vitro ADME and selectivity against human kinases. Initial in vivo testing has revealed good oral bioavailability in a mouse PK study and modest in vivo efficacy in a Plasmodium berghei mouse model of malaria.
FUSED HETEROCYCLIC COMPOUNDS FOR USE IN THE TREATMENT OF MALARIA
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Page/Page column 101, (2011/09/19)
A first aspect of the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt or ester thereof, wherein: R1 is -NR3R4 or -OR5; R2 is selected from aryl, heteroaryl, fused aryl- heterocycloalkyl and fused heteroaryl-heterocycloalkyl each of which may be optionally substituted by one or more R8 groups; R3 is H or alkyl; R4 is: (i) cycloalkyl optionally substituted by one or more -NR11R12, -NHCO2R11, -NHCOR11 and -NHSO2R11 groups; or (ii) -(CH2)n-heterocycloalkyl, wherein said heterocycloalkyl is a 4, 5 or 6-membered nitrogen-containing group optionally containing one or more CO groups, wherein said heterocycloalkyl is optionally substituted by one or more one or more (CH2)nR7 groups; (iii) -(CH2)n-heteroaryl, wherein said heteroaryl group is optionally substituted by one or more R7 groups; or (iv) alkyl substituted by one or more -NR11R12groups; or R3 and R4 are linked together with the nitrogen to which they are attached to form a 4, 5 or 6-membered heterocycloalkyl group optionally containing one or two further groups selected from CO, O, N and S, and which is optionally further substituted by one or more R7 groups; R5 is selected from alkyl, -(CH2)n-heteroaryl and -(CH2)n-heterocycloalkyl, wherein said heteroaryl and heterocycloalkyl groups are each optionally substituted by one or more R7 groups; each R11 and R12 is independently H or alkyl; and each n is independently an integer from O to 6; for use in treating or preventing a disorder associated with CDPK. Further aspects relate to the use of said compounds in the treatment of various therapeutic disorders, and more particularly as inhibitors of PfCDPK1.
