ABSTRACT:Cytochrome P450 (P450) induction is one of the factors that can affect the pharmacokinetics of a drug molecule upon multiple dosing, and it can result in pharmacokinetic drug-drug interactions with coadministered drugs causing potential therapeutic failures. In recent years, various in vitro assays have been developed and used routinely to assess the potential for drug-drug interactions due to P450 induction. There is a desire from the pharmaceutical industry and regulatory agencies to harmonize assay methodologies, data interpretation, and the design of clinical drug-drug interaction studies. In this article, a team of 10 scientists from nine Pharmaceutical Research and Manufacturers of America (PhRMA) member companies conducted an anonymous survey among PhRMA companies to query current practices with regards to the conduct of in vitro induction assays, data interpretation, and clinical induction study practices. The results of the survey are presented in this article, along with reviews of current methodologies of in vitro assays and in vivo studies, including modeling efforts in this area. A consensus recommendation regarding common practices for the conduct of P450 induction studies is included.The convergence of recent advances in molecular biology and genomics, higher throughput chemical synthesis, and automated highthroughput in vitro enzyme and cell-based assays to assess biological activity has led to shorter lead identification and optimization times in drug research. However, these breakthroughs have not yet translated into success in drug development. Surveys suggest that in the last several years, the number of New Drug Applications submitted to regulatory agencies has declined and that the poor success rate during drug development is to some extent due to late-stage failures. It is important that novel and innovative approaches are used for assessing the risks and benefits of new molecular entities (NMEs) early in the research and development life cycle to minimize late-stage attrition.Based on a survey conducted in 2004, the major factors for compound attrition during clinical development are lack of efficacy, toxicity, and safety, and suboptimal pharmacokinetics and/or bioavailability, with the remaining failures due to financial and/or commercial reasons (Kola and Landis, 2004). In that survey, one notable observation was the reduction of compound attrition due to pharmacokinetic and/or bioavailability issues from pre-1991 to the period be- ABBREVIATIONS: NME, new molecular entity; P450, cytochrome P450; DDI, drug-drug interaction; RIF, rifampicin; PhRMA, Pharmaceutical Research and Manufacturers of America; AhR, aryl hydrocarbon receptor; CAR, constitutive androstane receptor; PXR, pregnane X receptor; UGT, uridine diphosphate glucuronosyl transferase; FXR, farnesyl X receptor; PPAR, peroxisome proliferator-activated receptor; VDR, vitamin D receptor; Nrf2, nuclear factor erythroid 2-related factor 2; LBD, ligand binding domain; hPXR, human PXR; SR12813, tetra-ethyl 2-(3,5-di-tertbutyl...

The discovery and SAR of ketopiperazino methylazaindole factor Xa inhibitors are described. Structure-activity data suggesting that this class of inhibitors does not bind in the canonical mode were confirmed by an X-ray crystal structure showing the neutral haloaromatic bound in the S(1) subsite. The most potent azaindole, 33 (RPR209685), is selective against related serine proteases and attains higher levels of exposure upon oral dosing than comparable benzamidines and benzamidine isosteres. Compound 33 was efficacious in the canine AV model of thrombosis.

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The discovery and some of the basic structure-activity relationships of a series of novel nonpeptide inhibitors of blood coagulation Factor Xa is described. These inhibitors are functionalized beta-alanines, exemplified by 2a. Docking experiments placing 2a in the active site of Factor Xa implied that the most expeditious route to enhancing in vitro potency was to modify the group occupying the S3 site of the enzyme. Increasing the hydrophobic contacts between the inhibitor and the enzyme in this region led to 8, which has served as the prototype for this series. In addition, an enantioselective synthesis of these substituted beta-alanines was also developed.

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1 We compared the antithrombotic ecacy of a potent factor Xa inhibitor, FXV673, to heparin and RPR109891, a GPIIb/IIIa antagonist, when used as adjunctive therapy in a canine model of rt-PA-induced coronary thrombolysis. 2 Thrombus formation was induced by electrolytic injury to stenosed coronary artery. After thrombotic occlusion, a 135 min infusion of saline (n=8) , i.v.) was administered to all animals. Fifteen minutes after the start of drug infusion, rt-PA was administered (100 mg kg 71 +20 mg kg 71 min 71 for 60 min). 3 The incidence of reperfusion in the high dose FXV673 (8/8, 100%) was signi®cantly greater than that in the heparin group (4/8, 50%), with a trend to faster reperfusion (23+5 min for FXV673 versus 41+11 min for heparin). Only 2/8 (25%) of the vessels reoccluded in the high dose FXV673 group, compared to 4/4 (100%) and 5/5 (100%) vessels in the heparin and RPR109891 groups, respectively (P50.05). 4 Throughout the protocol, blood¯ow was higher in the FXV673 treated group compared to other groups. FXV673 enhanced vessel patency in a dose-dependent manner. 5 Compared to vehicle and heparin groups, the thrombus mass was decreased by 60% in the high dose FXV673. FXV673, heparin and RPR109891 increased the bleeding time by 2.7, 1.7 and 4 fold, and APTT by 2.8, 2.7 and 1.2 fold, respectively. 6 In conclusion, FXV673 is more eective than heparin and at least as eective as RPR109891 when used as an adjunct during rt-PA-induced coronary thrombolysis.

The discovery of a series of non-peptide factor Xa (FXa) inhibitors incorporating 3-(S)-amino-2-pyrrolidinone as a central template is described. After identifying compound 4, improvements in in vitro potency involved modifications of the liphophilic group and optimizing the angle of presentation of the amidine group to the S1 pocket of FXa. These studies ultimately led to compound RPR120844, a potent inhibitor of FXa (K(i) = 7 nM) which shows selectivity for FXa over trypsin, thrombin, and several fibrinolytic serine proteinases. RPR120844 is an effective anticoagulant in both the rat model of FeCl(2)-induced carotid artery thrombosis and the rabbit model of jugular vein thrombus formation.