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Torsten Hoffmann

Bio: Torsten Hoffmann is an academic researcher from Hoffmann-La Roche. The author has contributed to research in topics: Trifluoromethyl & Alkyl. The author has an hindex of 27, co-authored 112 publications receiving 4598 citations. Previous affiliations of Torsten Hoffmann include Scripps Research Institute & Ford Motor Company.


Papers
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Journal ArticleDOI
TL;DR: The current status, strengths, and weaknesses of peptides as medicines and the emerging new opportunities in peptide drug design and development are discussed.

2,136 citations

Journal ArticleDOI
16 May 2002-Nature
TL;DR: In this paper, a drug called R-1-[6]-R-2-carboxy-pyrrolidin-1-yl]-6-oxohexanoyl]-pyrroleidin]-2-Carboxylic acid (R-1]-6-[R]-R]-Pyrrolidine-2]-carboxyl acid was developed to remove SAP from human amyloid P component.
Abstract: The normal plasma protein serum amyloid P component (SAP) binds to fibrils in all types of amyloid deposits, and contributes to the pathogenesis of amyloidosis. In order to intervene in this process we have developed a drug, R-1-[6-[R-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid, that is a competitive inhibitor of SAP binding to amyloid fibrils. This palindromic compound also crosslinks and dimerizes SAP molecules, leading to their very rapid clearance by the liver, and thus produces a marked depletion of circulating human SAP. This mechanism of drug action potently removes SAP from human amyloid deposits in the tissues and may provide a new therapeutic approach to both systemic amyloidosis and diseases associated with local amyloid, including Alzheimer's disease and type 2 diabetes.

522 citations

Journal ArticleDOI
19 Dec 1997-Science
TL;DR: Structural and mechanistic studies show that when the selection criteria of the immune system are changed, catalytic antibodies that have the efficiency of natural enzymes evolve, but the catalytic antibody are much more accepting of a wide range of substrates.
Abstract: Structural and mechanistic studies show that when the selection criteria of the immune system are changed, catalytic antibodies that have the efficiency of natural enzymes evolve, but the catalytic antibodies are much more accepting of a wide range of substrates. The catalytic antibodies were prepared by reactive immunization, a process whereby the selection criteria of the immune system are changed from simple binding to chemical reactivity. This process yielded aldolase catalytic antibodies that approximated the rate acceleration of the natural enzyme used in glycolysis. Unlike the natural enzyme, however, the antibody aldolases catalyzed a variety of aldol reactions and decarboxylations. The crystal structure of one of these antibodies identified the reactive lysine residue that was selected in the immunization process. This lysine is deeply buried in a hydrophobic pocket at the base of the binding site, thereby accounting for its perturbed pKa.

363 citations

Journal ArticleDOI
TL;DR: This paper describes the substrate specificity, synthetic scope, and efficiency of aldolase catalytic antibodies 38C2 and 33F12, which use the enamine mechanism common to the natural Class I a Aldolase enzymes.
Abstract: This paper describes the substrate specificity, synthetic scope, and efficiency of aldolase catalytic antibodies 38C2 and 33F12. These antibodies use the enamine mechanism common to the natural Class I aldolase enzymes. Substrates for these catalysts, 23 donors and 16 acceptors, have been identified. The aldol acceptor specificity is expected to be much broader than that defined here since all aldehydes tested, with the exception polyhydroxylated aldehydes, were substrates for the antibodies. 38C2 and 33F12 have been shown to catalyze intermolecular ketone−ketone, ketone−aldehyde, aldehyde−ketone, and aldehyde−aldehyde aldol addition reactions and in some cases to catalyze their subsequent dehydration to yield aldol condensation products. Substrates for intramolecular aldol reactions have also been defined. With acetone as the aldol donor substrate a new stereogenic center is formed by attack on the si-face of the aldehyde with ee's in most cases exceeding 95%. With hydroxyacetone as the donor substrate, ...

196 citations

Journal ArticleDOI
TL;DR: There has been a paradigm shift in the underlying computational chemistry that drives chemical space search applications, incorporating intelligent reaction knowledge into their core so that they can readily deliver commercially available molecules as nearest neighbor hits from within giant virtual spaces.

130 citations


Cited by
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Journal ArticleDOI
TL;DR: Information is provided about CRP as a protein and an acute-phase reactant, and a knowledge-based framework for interpretation and analysis of clinical observations of CRP in relation to cardiovascular and other diseases, that identifies it as a possible therapeutic target.
Abstract: In the mid 1990s, immunoassays for C-reactive protein (CRP), with greater sensitivity than those previously in routine use, revealed that increased CRP values, even within the range previously considered normal, strongly predict future coronary events. These findings triggered widespread interest, especially, remarkably, in the US, where the clinical use of CRP measurement had been largely ignored for about 30 years. CRP production is part of the nonspecific acute-phase response to most forms of inflammation, infection, and tissue damage and was therefore considered not to provide clinically useful information. Indeed, CRP values can never be diagnostic on their own and can only be interpreted at the bedside, in full knowledge of all other clinical and pathological results. However, they can then contribute powerfully to management, just as universal recording of the patient’s temperature, an equally nonspecific parameter, is of great clinical utility. The present torrent of studies of CRP in cardiovascular disease and associated conditions is facilitated by the ready commercial availability of automated CRP assays and of CRP itself as a research reagent. However, unlike the earlier rejection in the US of CRP as an empirical test because of its perceived lack of specificity, the current enthusiasm over CRP in cardiovascular disease is widely characterized by failure to recognize appropriately the nonspecific nature of the acute-phase response, and by lack of critical biological judgment. Quality control of the source, purity, and structural and functional integrity of the CRP, and the relevance of experimental design before ascribing pathophysiological functions, are also often ignored. This article provides information about CRP as a protein and an acute-phase reactant, and a knowledge-based framework for interpretation and analysis of clinical observations of CRP in relation to cardiovascular and other diseases. We also review the properties of CRP, its possible role in pathogenesis of disease, and our own observations that identify it as a possible therapeutic target.

3,814 citations

Journal ArticleDOI
TL;DR: The finding that the amino acid proline is an effective asymmetric catalyst for the direct aldol reaction between unmodified acetone and a variety of aldehydes is reported.
Abstract: Most enzymatic transformations have a synthetic counterpart. Often though, the mechanisms by which natural and synthetic catalysts operate differ markedly. The catalytic asymmetric aldol reaction as a fundamental C-C bond forming reaction in chemistry and biology is an interesting case in this respect. Chemically, this reaction is dominated by approaches that utilize preformed enolate equivalents in combination with a chiral catalyst.1 Typically, a metal is involved in the reaction mechanism.1d Most enzymes, however, use a fundamentally different strategy and catalyze the direct aldolization of two unmodified carbonyl compounds. Class I aldolases utilize an enamine based mechanism,2 while Class II aldolases mediate this process by using a zinc cofactor.3 The development of aldolase antibodies that use an enamine mechanism and accept hydrophobic organic substrates has demonstrated the potential inherent in amine-catalyzed asymmetric aldol reactions.4 Recently, the first small-molecule asymmetric class II aldolase mimics have been described in the form of zinc, lanthanum, and barium complexes.5,6 However, amine-based asymmetric class I aldolase mimics have not been described in the literature.7 Here we report our finding that the amino acid proline is an effective asymmetric catalyst for the direct aldol reaction between unmodified acetone and a variety of aldehydes. Recently we developed broad scope aldolase antibodies that show very high enantioselectivities, have enzymatic rate accelerations, and use the enamine mechanism of class I aldolases.4 During the course of these studies, we found that one of our aldolase catalytic antibodies (Aldolase Antibody 38C2, Aldrich) is an efficient catalyst for enantiogroup-differentiating aldol cyclodehydrations of 2,6-heptanediones to give cyclohexenones, including the Wieland-Miescher ketone.8,9 These intramolecular reactions are also catalyzed by proline (Hajos-Eder-Sauer-Wiechert reaction)10 and it has been postulated that they proceed via an enamine mechanism.11 However, the proline-catalyzed direct intermolecular asymmetric aldol reaction has not been described. Further, there are no asymmetric small-molecule aldol catalysts that use an enamine mechanism.7 Based on our own results and Shibasaki’s work on lanthanum-based small-molecule aldol catalysts,4,6 we realized the great potential of catalysts for the direct asymmetric aldol reaction. We initially studied the reaction of acetone with 4-nitrobenzaldehyde. Reacting proline (30 mol %) in DMSO/acetone (4:1) with 4-nitrobenzaldehyde at room temperature for 4 h furnished aldol product (R)-1 in 68% yield and 76% ee (eq 1). This result

2,283 citations

Journal Article
01 Jan 2004-Nature
TL;DR: The authors showed that post-prandial elevation of PYY3-36 may act through the arcuate nucleus Y2R to inhibit feeding in a gut-hypothalamic pathway.
Abstract: Food intake is regulated by the hypothalamus, including the melanocortin and neuropeptide Y (NPY) systems in the arcuate nucleus. The NPY Y2 receptor (Y2R), a putative inhibitory presynaptic receptor, is highly expressed on NPY neurons in the arcuate nucleus, which is accessible to peripheral hormones. Peptide YY3-36 (PYY3-36), a Y2R agonist, is released from the gastrointestinal tract postprandially in proportion to the calorie content of a meal. Here we show that peripheral injection of PYY3-36 in rats inhibits food intake and reduces weight gain. PYY3-36 also inhibits food intake in mice but not in Y2r-null mice, which suggests that the anorectic effect requires the Y2R. Peripheral administration of PYY3-36 increases c-Fos immunoreactivity in the arcuate nucleus and decreases hypothalamic Npy messenger RNA. Intra-arcuate injection of PYY3-36 inhibits food intake. PYY3-36 also inhibits electrical activity of NPY nerve terminals, thus activating adjacent pro-opiomelanocortin (POMC) neurons. In humans, infusion of normal postprandial concentrations of PYY3-36 significantly decreases appetite and reduces food intake by 33% over 24 h. Thus, postprandial elevation of PYY3-36 may act through the arcuate nucleus Y2R to inhibit feeding in a gut–hypothalamic pathway.

1,960 citations

Journal ArticleDOI
TL;DR: Compounds Currently in Phase II−III Clinical Trials of Major Pharmaceutical Companies: New Structural Trends and Therapeutic Areas is presented.
Abstract: Compounds Currently in Phase II−III Clinical Trials of Major Pharmaceutical Companies: New Structural Trends and Therapeutic Areas Yu Zhou,† Jiang Wang,† Zhanni Gu,† Shuni Wang,† Wei Zhu,† Jose ́ Luis Aceña,*,‡,§ Vadim A. Soloshonok,*,‡,∥ Kunisuke Izawa,* and Hong Liu*,† †Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China ‡Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV/EHU, Paseo Manuel Lardizab́al 3, 20018 San Sebastiań, Spain Department of Organic Chemistry, Autońoma University of Madrid, Cantoblanco, 28049 Madrid, Spain IKERBASQUE, Basque Foundation for Science, María Díaz de Haro 3, 48013 Bilbao, Spain Hamari Chemicals Ltd., 1-4-29 Kunijima, Higashi-Yodogawa-ku, Osaka, Japan 533-0024

1,740 citations