The potency of oxalyl amino acid derivatives as inhibitors of prolyl 4-hydroxylase was studied in vitro, in isolated microsomes and in chicken embryonic-tissue culture. These compounds represent structural analogues of 2-oxoglutarate in which the -CH2- moiety at C-3 is replaced by -NH-, with or without further structural modifications. The most efficient inhibitor of purified prolyl 4-hydroxylase was oxalylglycine. Its mode of inhibition was competitive with respect to 2-oxoglutarate. The Ki value varied between 1.9 and 7.8 microM, depending on the variable substrate used. Oxalylalanine inhibited purified enzyme with a Ki of 40 microM. Other oxalyl amino acid derivatives showed little inhibitory activity. In microsomes isolated from embryonic chicken bone, oxalylglycine and oxalylalanine inhibited prolyl hydroxylation with IC50 values of 23 and 120 microM respectively. Dimethyloxalylglycine was not an inhibitor of purified prolyl 4-hydroxylase and only weakly active in the microsomal system, but efficiently suppressed hydroxyproline synthesis in embryonic chicken calvaria and lung. The data suggest that dimethyloxalyl amino acids are converted into active inhibitors in intact cells, most likely in the cytoplasmic compartment.

During the toxicological examination of the fibrosuppressive agent, Lufironil (INN), in rats a dose-dependent positive reaction for urinary bilirubin was observed. This positive reaction was found in quantitative assays, and when using test strips.The positive reaction for bilirubin in these assay systems was caused by a metabolite of Lufironil. It was not due to drug toxicity, and it was not caused by any endogenous substrate produced under the influence of Lufironil.The compound responsible for this reaction was isolated by HPLC and its structure determined by spectroscopic methods. The structure was confirmed by synthesis, starting from pyridine-2,4-dicarboxylate. The synthesized compound and the compound in urine gave an identical reaction with the test reagent for bilirubin.

A group of 43 optically active sodium carboxylates (11a-qq and the corresponding lactones 4 were prepared from respective phenols 8 according to Schemes I-III. Phenols 8 were synthesized from commercially available compounds according to Schemes IV-IX. A number of these HMG-CoA reductase inhibitors 11 exceeded mevinolin's activity in vitro (Tables II and III). Selected lactones 4 effectively inhibited hepatic "de novo" cholesterol synthesis in rats in vivo (Table IV). After po administration to rabbits, 4ff(11ff), 4hh, and notably 11jj reduced plasma cholesterol levels more potently than mevinolin (Table V). Whereas 4ff(11ff) displayed the slight superiority expected according to in vitro data, 4hh and 11jj were considerably more potent than expected. Each of these compounds had only moderate activity after po administration to dogs (Table VI). Compound di-11ii, a hybrid of the structural elements of probucol and HMG-CoA reductase inhibitors, after po administration to rats decreased serum lipoproteins and increased HDL/LDL ratio better than probucol (Table VII). HMG-CoA reductase inhibitor 11ll and phenolic building blocks 8, notably 8jj and 8kk, inhibited LDL oxidation in vitro (Table VIII). Chemical structure-activity relationships (Table IX) and the pharmacological profile of phenoxy-type inhibitors 11 diverged from those of known HMG-CoA reductase inhibitors.

The biochemical and morphological consequences of procollagen prolyl 4-hydroxylase inhibition by pyridine-2,4-dicarboxylic acid (2,4-PDCA) and its diethyl ester (diethyl-2,4-PDC) were studied in chick-embryo calvaria, which predominantly synthesize type I collagen. Half-maximal inhibition of tissue hydroxyproline formation required 650 microM-2,4-PDCA, whereas the Ki with respect to chicken prolyl 4-hydroxylase in vitro was 2 microM. In contrast, half-maximal inhibition was caused by 10 microM-diethyl-2,4-PDC in the intact calvaria, although chicken prolyl 4-hydroxylase in vitro was not inhibited even at 1 mM. The collagenous material produced in the presence of diethyl-2,4-PDC showed an altered ‘melting’ profile and a lowering of the transition temperature by 10 degrees C, indicating misalignment and thermal instability of its triple-helical structure. Amount and electrophoretic mobility of procollagen type I chains were increased in a dose-dependent manner. The amounts of partially processed species and alpha-chains were decreased, without change in mobility. This marked effect on procollagen-collagen conversion in the intact calvaria suggests that the underhydroxylated collagenous material generated in the presence of diethyl-2,4-PDC is resistant to or acts as endogenous secondary inhibitor of type I procollagen N-proteinase. Electron microscopy of treated calvaria cells showed dilated rough endoplasmic reticulum and numerous phagolysosomes, indicating intracellular retention and lysosomal degradation of the newly synthesized underhydroxylated collagenous material. In summary, these results identify 2,4-PDCA and diethyl-2,4-PDC as the first prolyl 4-hydroxylase-directed inhibitor/proinhibitor pair that affects intra- and extra-cellular events during collagen formation.

The studies were performed in healthy male rats and in one male dog after oral and intravenous administration of [2-carbamoyl-14C]HOE 077. HOE 077 wa rapidly and completely absorbed after oral administration. In blood, tmax was at about 0.5 h and cmax 2.63 +/- 0.92 micrograms equivalents/g in rats (5 mg/kg), and 18.1 micrograms equivalents/g in the dog (15 mg/kg). The predominant half-lives for total radioactivity were in the range of 1 h in the rats and 2 h in the dog, independent of the route of administration. The radioactivity was distributed throughout the body. The highest concentrations were detected in kidneys and liver. Urine (75% of dose) was the main route of excretion after oral and intravenous administration. The radioactivity was almost entirely eliminated 2 days after administration. The compound was intensively metabolized by rat and dog. While the parent compound was the major component in plasma at early time after dosage, more than ten metabolites, accompanied by only small amounts of original substance, were detected in the urine of the first study day. In faeces only metabolites were found. The known metabolites are assumed to be formed by oxidative degradation of the alkylic side chains of the molecule, preferably that in the 2-position of the pyridine ring. The main metabolite in the dog urine was a 2-hydroxyethyl derivative (M4), and in the rat a hippuric acid analogue of HOE 077 (M6). The pyridine carboxylic acid in 2-position of the side chain of HOE 077 (M2) was the predominant metabolite in faeces of rat and dog. In both animal species, more than 80% of the administered radioactivity had been identified. In rats with liver damage caused by treatment with CCl4 the amount of parent compound increased and the rates of formation of metabolites were lower than in normal rats. This can be interpreted as a consequence of the diminished number of hepatocytes able to metabolize HOE 077.

S 0885 and HOE 077 inhibit CCl4-induced liver fibrosis in rats, as shown by significantly reduced hydroxyproline content of the liver and improved liver histology. Mortality of drug-treated animals is significantly diminished. Serum collagen parameters correlate well with the hydroxyproline content of the liver and can be used as noninvasive markers for the fibrotic process. HOE 077 is a proinhibitor, which by itself does not inhibit prolyl 4-hydroxylase. HOE 077 is well absorbed from the gastrointestinal tract. It is taken up by rat liver and is converted to the active metabolites. At a concentration of 1 mM, HOE 077 does not affect collagen synthesis in human fibroblasts, bovine chondrocytes and chicken calvaria. At therapeutic doses the compound does not reduce collagen content of kidney, lung, aorta, femur epiphysis, skin and tendon of the rat, validating the high specifity of the liver selective prodrug/inhibitor conversion. From animal experiments, a human daily dose of 0.5-1 g can be extrapolated.

Lactones of pyridine- and pyrimidine-substituted 3,5-dihydroxy-6-heptenoic (-heptanoic) acids 2-4 have been synthesized. Extensive exploration of structure-activity relationships led to several compounds exceeding the inhibitory activity of mevinolin (1b) on HMG-CoA reductase, both in vitro and in vivo. First clinical trials with 2i (HR 780) are in preparation.

HR 780 (1) a new HMG-CoA reductase inhibitor has been synthesized stereoselectively starting from L-malic acid. Wittig olefination employing phosphonium halides, phosphonates and phosphane oxides have been investigated.

ChemInformVolume 21, Issue 10 Reviews ChemInform Abstract: Synthesis of Chiral Lipid-Lowering Agents Derived from Natural Products E. BAADER, E. BAADER Edited by Szantay, Cs.; Akad. Kiado, Budapest, Hung.Search for more papers by this authorW. BARTMANN, W. BARTMANN Edited by Szantay, Cs.; Akad. Kiado, Budapest, Hung.Search for more papers by this authorG. BECK, G. BECK Edited by Szantay, Cs.; Akad. Kiado, Budapest, Hung.Search for more papers by this authorA. BERGMANN, A. BERGMANN Edited by Szantay, Cs.; Akad. Kiado, Budapest, Hung.Search for more papers by this authorE. GRANZER, E. GRANZER Edited by Szantay, Cs.; Akad. Kiado, Budapest, Hung.Search for more papers by this authorH. JENDRALLA, H. JENDRALLA Edited by Szantay, Cs.; Akad. Kiado, Budapest, Hung.Search for more papers by this authorB. VON KEREKJARTO, B. VON KEREKJARTO Edited by Szantay, Cs.; Akad. Kiado, Budapest, Hung.Search for more papers by this authorK. KESSELER, K. KESSELER Edited by Szantay, Cs.; Akad. Kiado, Budapest, Hung.Search for more papers by this authorR. KRAUSE, R. KRAUSE Edited by Szantay, Cs.; Akad. Kiado, Budapest, Hung.Search for more papers by this authorET AL. ET AL., ET AL. ET AL. Edited by Szantay, Cs.; Akad. Kiado, Budapest, Hung.Search for more papers by this author E. BAADER, E. BAADER Edited by Szantay, Cs.; Akad. Kiado, Budapest, Hung.Search for more papers by this authorW. BARTMANN, W. BARTMANN Edited by Szantay, Cs.; Akad. Kiado, Budapest, Hung.Search for more papers by this authorG. BECK, G. BECK Edited by Szantay, Cs.; Akad. Kiado, Budapest, Hung.Search for more papers by this authorA. BERGMANN, A. BERGMANN Edited by Szantay, Cs.; Akad. Kiado, Budapest, Hung.Search for more papers by this authorE. GRANZER, E. GRANZER Edited by Szantay, Cs.; Akad. Kiado, Budapest, Hung.Search for more papers by this authorH. JENDRALLA, H. JENDRALLA Edited by Szantay, Cs.; Akad. Kiado, Budapest, Hung.Search for more papers by this authorB. VON KEREKJARTO, B. VON KEREKJARTO Edited by Szantay, Cs.; Akad. Kiado, Budapest, Hung.Search for more papers by this authorK. KESSELER, K. KESSELER Edited by Szantay, Cs.; Akad. Kiado, Budapest, Hung.Search for more papers by this authorR. KRAUSE, R. KRAUSE Edited by Szantay, Cs.; Akad. Kiado, Budapest, Hung.Search for more papers by this authorET AL. ET AL., ET AL. ET AL. Edited by Szantay, Cs.; Akad. Kiado, Budapest, Hung.Search for more papers by this author First published: March 6, 1990 https://doi.org/10.1002/chin.199010359Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume21, Issue10March 6, 1990 RelatedInformation

A series of 7-(1H-pyrrol-3-yl)-substituted-3,5-dihydroxyhept-6(E)- enoates (-heptanoates) 1 and 2 have been prepared and tested for inhibiti 3-hydroxy-3-methylglutaryl-coenzyme A reductase. The most potent compounds exceeded mevinolin's activity in vitro and in vivo.

The synthesis of a new fluoro-substituted 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor 3 in high optical purity via addition of the chiral enolate 12 to fluoro aldehyde 8Z is described.

It is described for obtaining derivatives optically active 3 ACID PROCESS - DESMETILMEVALONICO of formula I (acid derivatives 3.5 - dihydroxycarboxylic) or formula II ((BETA) - hydroxy - LATONA) wherein R, R1 YY HAVE THE SIGNIFICANCE DADA. IN ADDITION, PATENTS AFFECTS aldehydes of formula XII wherein M represents protecting groups DICE.

The synthesis of a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor starting from 4,4′-difluorobenzophenone is described.

PURPOSE: To obtain the compound useful as 3-hydroxy-3-methylglythallyl coenzyme A reductase inhibitor in a simplified and shortened process by using a specific diol ester as starting materials. CONSTITUTION: The compound of formula II (R 2 is OH-protecting group) is obtained by allowing the compound of formula I (R 1 is alkyl) to condense with tert.butylacetate after protecting prim.alcohol and then allowing thereof to reduce. Then an intermediate of formula III is obtained by removing a protecting group R 2 after introducing a suitable protecting group to 1,3-diol. The compound of formula VI (Y is CH=CH or CH 2 -CH 2 , R 1 is H, metal cation or alkyl) is obtained by allowing the intermediate to convert to olefin derivative of formula IV [R is formula V (Z is CH or N; R 3 to R 5 are each hydrocarbon, phenyl or the like], hydrolyzing thereof and optionally adding hydrogen and then allowing thereof to convert to acid or salt. COPYRIGHT: (C)1989,JPO

ChemInformVolume 19, Issue 47 Organoelement Compounds ChemInform Abstract: Syntheses of (4R)-Silyloxy-(6S)-iodomethyltetrahydropyran-2-one (II) and Its Enantiomer, Building Blocks for HMG-CoA Reductase Inhibitors. E. BAADER, E. BAADER Hoechst AG, Pharma Forschung, D-6230 Frankfurt/MainSearch for more papers by this authorW. BARTMANN, W. BARTMANN Hoechst AG, Pharma Forschung, D-6230 Frankfurt/MainSearch for more papers by this authorG. BECK, G. BECK Hoechst AG, Pharma Forschung, D-6230 Frankfurt/MainSearch for more papers by this authorA. BERGMANN, A. BERGMANN Hoechst AG, Pharma Forschung, D-6230 Frankfurt/MainSearch for more papers by this authorH.-W. FEHLHABER, H.-W. FEHLHABER Hoechst AG, Pharma Forschung, D-6230 Frankfurt/MainSearch for more papers by this authorH. JENDRALLA, H. JENDRALLA Hoechst AG, Pharma Forschung, D-6230 Frankfurt/MainSearch for more papers by this authorK. KESSELER, K. KESSELER Hoechst AG, Pharma Forschung, D-6230 Frankfurt/MainSearch for more papers by this authorR. SARIC, R. SARIC Hoechst AG, Pharma Forschung, D-6230 Frankfurt/MainSearch for more papers by this authorH. + SCHUESSLER, H. + SCHUESSLER Hoechst AG, Pharma Forschung, D-6230 Frankfurt/MainSearch for more papers by this authorV. TEETZ, V. TEETZ Hoechst AG, Pharma Forschung, D-6230 Frankfurt/MainSearch for more papers by this authorM. WEBER, M. WEBER Hoechst AG, Pharma Forschung, D-6230 Frankfurt/MainSearch for more papers by this authorG. WESS, G. WESS Hoechst AG, Pharma Forschung, D-6230 Frankfurt/MainSearch for more papers by this author E. BAADER, E. BAADER Hoechst AG, Pharma Forschung, D-6230 Frankfurt/MainSearch for more papers by this authorW. BARTMANN, W. BARTMANN Hoechst AG, Pharma Forschung, D-6230 Frankfurt/MainSearch for more papers by this authorG. BECK, G. BECK Hoechst AG, Pharma Forschung, D-6230 Frankfurt/MainSearch for more papers by this authorA. BERGMANN, A. BERGMANN Hoechst AG, Pharma Forschung, D-6230 Frankfurt/MainSearch for more papers by this authorH.-W. FEHLHABER, H.-W. FEHLHABER Hoechst AG, Pharma Forschung, D-6230 Frankfurt/MainSearch for more papers by this authorH. JENDRALLA, H. JENDRALLA Hoechst AG, Pharma Forschung, D-6230 Frankfurt/MainSearch for more papers by this authorK. KESSELER, K. KESSELER Hoechst AG, Pharma Forschung, D-6230 Frankfurt/MainSearch for more papers by this authorR. SARIC, R. SARIC Hoechst AG, Pharma Forschung, D-6230 Frankfurt/MainSearch for more papers by this authorH. + SCHUESSLER, H. + SCHUESSLER Hoechst AG, Pharma Forschung, D-6230 Frankfurt/MainSearch for more papers by this authorV. TEETZ, V. TEETZ Hoechst AG, Pharma Forschung, D-6230 Frankfurt/MainSearch for more papers by this authorM. WEBER, M. WEBER Hoechst AG, Pharma Forschung, D-6230 Frankfurt/MainSearch for more papers by this authorG. WESS, G. WESS Hoechst AG, Pharma Forschung, D-6230 Frankfurt/MainSearch for more papers by this author First published: November 22, 1988 https://doi.org/10.1002/chin.198847205AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume19, Issue47November 22, 1988 RelatedInformation

Optically pure 4(R), 6(S)-iodolactone 1 was obtained from α-D-(+)-glucose in 17 steps with 17% overall yield. Its enantiomer 4(S), 6(R)-iodolactone 1′ was obtained from acetonedicarboxylic acid in 9 steps in 37% overall yield and with 70% ee. Key steps in the synthesis of 1′ are enzyme (PLE)-catalyzed saponification of prochiral di-n-propyl-3-hydroxyglutarate 7 and iodolactonization of 11 .

FEBS LettersVolume 214, Issue 2 p. 236-243 HypothesisFree Access Pyrroloquinoline quinone and molecules mimicking its functional domains Modulators of connective tissue formation? H.M. Hanauske-Abel, Corresponding Author H.M. Hanauske-Abel Laboratory of Human Biochemistry, Children's Hospital, Harvard Medical School, Boston, MA, USAH.M. Hanauske-Abel, Laboratory of Human Biochemistry, Enders Pediatric Research Building, The Children's Hospital Medical Center, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USASearch for more papers by this authorG. Tschank, G. Tschank Institute of Toxicology, J. Gutenberg University, Mainz, FRGSearch for more papers by this authorV. Günzler, V. Günzler Collagen Research Unit, Department of Medical Biochemistry, University of Oulu, FinlandSearch for more papers by this authorE. Baader, E. Baader Hoechst AG, Frankfurt, FRGSearch for more papers by this authorP. Gallop, P. Gallop Laboratory of Human Biochemistry, Children's Hospital, Harvard Medical School, Boston, MA, USASearch for more papers by this author H.M. Hanauske-Abel, Corresponding Author H.M. Hanauske-Abel Laboratory of Human Biochemistry, Children's Hospital, Harvard Medical School, Boston, MA, USAH.M. Hanauske-Abel, Laboratory of Human Biochemistry, Enders Pediatric Research Building, The Children's Hospital Medical Center, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USASearch for more papers by this authorG. Tschank, G. Tschank Institute of Toxicology, J. Gutenberg University, Mainz, FRGSearch for more papers by this authorV. Günzler, V. Günzler Collagen Research Unit, Department of Medical Biochemistry, University of Oulu, FinlandSearch for more papers by this authorE. Baader, E. Baader Hoechst AG, Frankfurt, FRGSearch for more papers by this authorP. Gallop, P. Gallop Laboratory of Human Biochemistry, Children's Hospital, Harvard Medical School, Boston, MA, USASearch for more papers by this author First published: April 20, 1987 https://doi.org/10.1016/0014-5793(87)80062-5Citations: 13AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat References 1 K.A. Piez, A.H. Reddi, Extracellular Matrix Biochemistry (1984), Elsevier Amsterdam, New York 2 B. Brodsky, E.F. Eikenberry, Methods Enzymol., 82, (1982), 127– 174. 3 C.H. Wu, C.B. Donovan, G.Y. Wu, J. Biol. 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