PubMed · 15296355
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Susanne Heinzl. 2004. [Folic acid antagonists pemetrexed].. https://pubmed.ncbi.nlm.nih.gov/15296355/
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BACKGROUND: Methotrexate, a folic acid antagonist with immunosuppressive properties, has been used to treat patients with primary biliary cirrhosis. The therapeutic responses to methotrexate in randomised clinical trials have been heterogeneous. OBJECTIVES: To assess the beneficial and harmful effects of methotrexate for patients with primary biliary cirrhosis. SEARCH STRATEGY: Relevant randomised clinical trials were identified by searching The Cochrane Hepato-Biliary Group Controlled Trials Register (June 2004), The Cochrane Central Register of Controlled Trials on The Cochrane Library (Issue 2, 2004), MEDLINE (January 1966 to August 2004), EMBASE (January 1980 to August 2004), and manual searches of bibliographies. We contacted authors of trials and pharmaceutical companies. SELECTION CRITERIA: Randomised clinical trials comparing methotrexate with placebo, no intervention, or another drug were included irrespective of blinding, language, year of publication, and publication status. DATA COLLECTION AND ANALYSIS: Our primary outcomes were mortality and mortality or liver transplantation. Dichotomous outcomes were reported as relative risk (RR) and hazard ratio (HR) if applicable. Continuous outcomes were reported as weighted mean difference (WMD). We examined intervention effects by using both a random-effects model and a fixed-effect model. Heterogeneity was investigated by subgroup analyses and sensitivity analyses. MAIN RESULTS: We identified four trials (370 patients) that compared methotrexate with placebo with or without ursodeoxycholic acid as co-intervention. One additional trial (87 patients) compared methotrexate with colchicine without and later with ursodeoxycholic acid as co-intervention. The methodological quality of the trials was low. We did not find significant effects of methotrexate on pruritus, fatigue, liver complications, liver biochemistry, liver histology, or adverse events. The pruritus score (WMD - 0.68, 95% CI - 1.11 to - 0.25), the levels of serum alkaline phosphatases (WMD - 0.41, 95% CI - 0.70 to - 0.12) and plasma immunoglobulin M (WMD - 0.47, 95% CI - 0.74 to - 0.20) were significantly lower in the patients receiving methotrexate. AUTHORS' CONCLUSIONS: Methotrexate increased mortality in patients with primary biliary cirrhosis. We do not recommend methotrexate for patients with primary biliary cirrhosis outside randomised trials.
2,4-Diamino-5-[3',4'-dimethoxy-5'-(5-carboxy-1-pentynyl)]benzylpyrimidine (6) and 2,4-diamino-5-[3',4'-dimethoxy-5'-(4-carboxyphenylethynyl)benzylpyrimidine (7) were synthesized from 2,4-diamino-5-(5'-iodo-3',4'-dimethoxybenzyl)pyrimidine (9) via a Sonogashira reaction with appropriate acetylenic esters followed by saponification, and were tested as inhibitors of dihydrofolate reductase (DHFR) from Pneumocystis carinii (Pc), Toxoplasma gondii (Tg), Mycobacterium avium (Ma), and rat in comparison with the widely used antibacterial agent 2,4-diamino-5-(3',4',5'-trimethoxybenzyl)pyrimidine (trimethoprim, TMP). The selectivity index (SI) for each compound was calculated by dividing its 50% inhibitory concentration (IC(50)) against rat DHFR by its IC(50) against Pc, Tg, or Ma DHFR. The IC(50) of 6 against Pc DHFR was 1.0 nM, with an SI of 5000. Compound 7 had an IC(50) of 8.2 nM against Ma DHFR, with an SI of 11000. By comparison, the IC(50) of TMP was 12000 nM against Pc, 300 nM against Ma, and 180000 against rat DHFR. The potency and selectivity values of 6 and 7 were not as high against Tg as they were against Pc or Ma DHFR, but nonetheless exceeded those of TMP. Because of the outstanding selectivity of 6 against Pc and of 7 against Ma DHFR, these novel analogues may be viewed as promising leads for further structure-activity optimization.
Pharmacophore hypotheses were developed for a series of 2,4-diamino-5-deazapteridine inhibitors of Mycobacterium avium complex (MAC) and human dihydrofolate reductase (hDHFR). Training sets consisting of 20 inhibitors were selected in each case on the basis of the information content of the structures and activity data as required by the HypoGen program in the Catalyst software. In the case of MAC DHFR inhibitors, the best pharmacophore in terms of statistics and predictive value consisted of four features: two hydrogen bond acceptors (HA), one hydrophobic (HY) feature, and one ring aromatic (RA) feature. The selected pharmacophore hypothesis yielded an rms deviation of 0.730 and a correlation coefficient of 0.967 with a cost difference (null cost minus total cost) of approximately 52. The pharmacophore was validated on a large set of test inhibitors. For the test series, a classification scheme was used to distinguish highly active from moderately active and inactive compounds on the basis of activity ranges. This classification scheme is more practical than actual estimated values because these values have no meaning for compounds yet to be tested except that they indicate whether the compounds will be active or inactive in a biological assay. For the training set, the success rate for predicting active and inactive compounds was 100%. For the test set, the success rate in predicting active compounds was greater than 92% while about 7% of the inactive compounds were predicted to be active. This successful prediction was further validated on three structurally diverse compounds active against MAC DHFR. Two compounds mapped well onto three of the four features of the pharmacophore. The third compound was mapped to all four features of the pharmacophore. This validation study provided confidence for the usefulness of the selected pharmacophore model to identify compounds with diverse structures from a database search. Comparison of pharmacophores for inhibitors of human and MAC DHFR is expected to reveal fundamental differences between these two pharmacophores that may be effectively exploited to identify and design compounds with high selectivity for MAC DHFR.