Farnesyl Protein Transferase Inhibitor ZARNESTRA&amp;#8482; R115777 - History of a Discovery

Venet, Marc; End, David W.; Angibaud, Patrick

doi:10.2174/1568026033452050

Cited by 73 publications

(51 citation statements)

References 13 publications

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“…It is fortuitous that compound 2.1 had lower inhibitory activity against most of the CYP isoforms than did the 2.2 enantiomer. For an imidazole-containing molecule, compound 2.1 has a good profile against hepatic CYP enzymes, consistent with what is known about tipifarnib (29).…”

Section: Discussionsupporting

confidence: 78%

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Pharmacological Characterization, Structural Studies, and In Vivo Activities of Anti-Chagas Disease Lead Compounds Derived from Tipifarnib

Buckner

Bahia

Suryadevara

et al. 2012

Antimicrob Agents Chemother

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g Chagas disease, caused by the protozoan pathogen Trypanosoma cruzi, remains a challenging infection due to the unavailability of safe and efficacious drugs. Inhibitors of the trypanosome sterol 14␣-demethylase enzyme (CYP51), including azole antifungal drugs, are promising candidates for development as anti-Chagas disease drugs. Posaconazole is under clinical investigation for Chagas disease, although the high cost of this drug may limit its widespread use. We have previously reported that the human protein farnesyltransferase (PFT) inhibitor tipifarnib has potent anti-T. cruzi activity by inhibiting the CYP51 enzyme. Furthermore, we have developed analogs that minimize the PFT-inhibitory activity and enhance the CYP51 inhibition. In this paper, we describe the efficacy of the lead tipifarnib analog compared to that of posaconazole in a murine model of T. cruzi infection. The plasma exposure profiles for each compound following a single oral dose in mice and estimated exposure parameters after repeated twice-daily dosing for 20 days are also presented. The lead tipifarnib analog had potent suppressive activity on parasitemia in mice but was unsuccessful at curing mice, whereas posaconazole as well as benznidazole cured 3 of 5 and 4 of 6 mice, respectively. The efficacy results are consistent with posaconazole having substantially higher predicted exposure than that of the tipifarnib analog after repeat twice-daily administration. Further changes to the tipifarnib analogs to reduce plasma clearance are therefore likely to be important. A crystal structure of a trypanosomal CYP51 bound to a tipifarnib analog is reported here and provides new insights to guide structure-based drug design for further optimized compounds.

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Section: Discussionsupporting

confidence: 78%

“…The preclinical drug candidate tipifarnib is an R enantiomer, having Ͼ100-fold-greater PFT-inhibitory activity than the corresponding S enantiomer (29). The tipifarnib analogs that we previously described were synthesized and tested as racemic mixtures (11)(12)(13).…”

Section: Pharmacokinetic Characterization Of Compound 2 and Posaconazmentioning

confidence: 99%

Pharmacological Characterization, Structural Studies, and In Vivo Activities of Anti-Chagas Disease Lead Compounds Derived from Tipifarnib

Buckner

Bahia

Suryadevara

et al. 2012

Antimicrob Agents Chemother

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“…Among numerous FPT inhibitors synthesised, two orally bioavailable agents, sarasar (formerly SCH66336) (Ganguly et al, 2001) and R115777 (tipifarnib, Zarnestra) (Venet et al, 2003), have advanced to Phase II/III clinical development. The latter agent is an orally bioavailable methyl-quinolone and belongs to the class of nonpeptidomimetic FPT inhibitors with a broad spectrum of preclinical antitumour activity Kelland et al, 2001;Smith et al, 2002).…”

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confidence: 99%

Phase I and pharmacokinetic study of irinotecan in combination with R115777, a farnesyl protein transferase inhibitor

et al. 2004

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The aims of this study were to determine the maximum-tolerated dose (MTD), toxicity profile, and pharmacokinetics of irinotecan given with oral R115777 (tipifarnib), a farnesyl protein transferase inhibitor. Patients were treated with escalating doses of irinotecan with interval-modulated dosing of R115777 (continuously or on days 1 -14, and repeated every 21 days). In total, 35 patients were entered onto the trial for a median duration of treatment of 43 days (range, 5 -224 days). Neutropenia and thrombocytopenia were the dose-limiting toxicities; other side effects were mostly mild. The MTD was established at R115777 300 mg b.i.d. for 14 consecutive days with irinotecan 350 mg m À2 given every 3 weeks starting on day 1. Three patients had a partial response and 14 had stable disease. In the continuous schedule, the area under the curves of irinotecan and its active metabolite SN-38 were 20.0% (P ¼ 0.004) and 38.0% (Po0.001) increased by R115777, respectively. Intermittent dosing of R115777 at a dose of 300 mg b.i.d. for 14 days every 3 weeks is the recommended dose of R115777 in combination with the recommended single-agent irinotecan dose of 350 mg m À2 .

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“…2-Quinolinones, which are also subunits of a range of natural products 31,32) and pharmaceuticals, [33][34][35][36][37] can be prepared via palladium-catalyzed intramolecular C-H amidation. Specifically, the treatment of N-tosyl-3,3-diphenylacrylamide (10a) with a catalytic amount of PdCl 2 along with a reoxidant such as 100 mol % Cu(OAc) 2 in DMSO afforded the cyclized product (Chart 5).…”

Section: )mentioning

confidence: 99%

Synthesis of Heterocyclic Compounds through Palladium-Catalyzed C–H Cyclization Processes

Inamoto

2013

CHEMICAL & PHARMACEUTICAL BULLETIN

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Herein, we describe our development of synthetic methods for heterocyclic compounds based on the palladium-catalyzed carbon-hydrogen bond (C-H) functionalization/intramolecular carbon-heteroatom (nitrogen or sulfur) bond formation process. By this C-H cyclization method, we efficiently prepared various N-heterocycles, including indazoles, indoles, and 2-quinolinones, as well as S-heterocycles such as benzothiazoles and benzo[b]thiophenes. Yields are typically good to high and good functional-group tolerance is observed for each process, thereby indicating that the method provides a novel, highly applicable synthetic route to the abovementioned biologically important heterocyclic frameworks. As an application of this approach, an auto-tandem-type, one-pot process involving the oxidative Heck reaction and subsequent C-H cyclization using cinnamamides and arylboronic acids as starting materials in the presence of a palladium catalyst was also developed for the rapid construction of the 2-quinolinone nucleus.

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Farnesyl Protein Transferase Inhibitor ZARNESTRA™ R115777 - History of a Discovery

Cited by 73 publications

References 13 publications

Pharmacological Characterization, Structural Studies, and In Vivo Activities of Anti-Chagas Disease Lead Compounds Derived from Tipifarnib

Pharmacological Characterization, Structural Studies, and In Vivo Activities of Anti-Chagas Disease Lead Compounds Derived from Tipifarnib

Phase I and pharmacokinetic study of irinotecan in combination with R115777, a farnesyl protein transferase inhibitor

Synthesis of Heterocyclic Compounds through Palladium-Catalyzed C–H Cyclization Processes

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