Second generation analogues of the cancer drug clinical candidate tipifarnib for anti-Chagas disease drug discovery.
We previously reported that the cancer drug clinical candidate tipifarnib kills the causative agent of Chagas disease, Trypanosoma cruzi, by blocking ergosterol biosynthesis at the level of inhibition of lanosterol 14alpha-demethylase. Tipifarnib is an inhibitor of human protein farnesyltransferase. We synthesized tipifarnib analogues that no longer bind to protein farnesyltransferase and display increased potency for killing parasites. This was achieved in a structure-guided fashion by changing the substituents attached to the phenyl group at the 4-position of the quinoline ring of tipifarnib and by replacing the amino group by OMe. Several compounds that kill Trypanosoma cruzi at subnanomolar concentrations and are devoid of protein farnesyltransferase inhibition were discovered. The compounds are shown to be advantageous over other lanosterol 14alpha-demethylase inhibitors in that they show only modest potency for inhibition of human cytochrome P450 (3A4). Since tipifarnib displays high oral bioavailability and acceptable pharmacokinetic properties, the newly discovered tipifarnib analogues are ideal leads for the development of drugs to treat Chagas disease.
Kraus
James M
JM
Department of Chemistry, University of Washington, Seattle, Washington 98195-7185, USA.
Tatipaka
Hari Babu
HB
McGuffin
Sarah A
SA
Chennamaneni
Naveen Kumar
NK
Karimi
Mandana
M
Arif
Jenifer
J
Verlinde
Christophe L M J
CL
Buckner
Frederick S
FS
Gelb
Michael H
MH
D016475:3T3 Cells; D019883:Alkyl and Aryl Transferases / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry; D014355:Chagas Disease / Q000188:drug therapy*; D051544:Cytochrome P-450 CYP3A / Q000737:chemistry; D065692:Cytochrome P-450 CYP3A Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D051379:Mice; D008958:Models, Molecular; D011485:Protein Binding; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D058886:Sterol 14-Demethylase; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014349:Trypanosoma cruzi / Q000187:drug effects
D000970:Antineoplastic Agents; C548418:CYP51A1 protein, human; D065692:Cytochrome P-450 CYP3A Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D007527:Isoenzymes; D015363:Quinolones; D014344:Trypanocidal Agents; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; C548415:Cyp51 protein, mouse; D058886:Sterol 14-Demethylase; C510163:CYP3A4 protein, human; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase; C402769:tipifarnib