Hans Peter Märki

Substituted piperidines: Highly potent renin inhibitors due to induced fit adaptation of the active site

The identification, synthesis and activity of a novel class of piperidine renin inhibitors is presented. The most active compounds show activities in the picomolar range and are among the most potent renin inhibitors ever identified.

Aleglitazar, a new, potent, and balanced dual PPARα/γ agonist for the treatment of type II diabetes

Design, synthesis, and SAR of novel alpha-alkoxy-beta-arylpropionic acids as potent and balanced PPARalphagamma coagonists are described. One representative thereof, Aleglitazar ((S)-2Aa), was chosen for clinical development. Its X-ray structure in complex with both receptors as well as its high efficacy in animal models of T2D and dyslipidemia are also presented.

Identification of the active‐site serine in human pancreatic lipase by chemical modification with tetrahydrolipstatin

A chemical modification approach was used in this study to identify the active site serine residue of human pancreatic lipase. Purified human pancreatic lipase was covalently modified by incubation with [3H], [14C]tetrahydrolipstatin (THL), a potent inhibitor of pancreatic lipase. The radiolabeled lipase was digested with thermolysin, and the peptides were separated by HPLC. A single THL‐peptide‐adduct was obtained which was identical to that obtained earlier from porcine pancreatic lipase. This pentapeptide with the sequence VIGHS is covalently bound to a THL molecule via the side chain hydroxyl group of the serine unit corresponding to Ser‐152 of the lipase. The selective cleavage of the THL‐serine bond by mild acid treatment resulted in the formation of the δ‐lactone Ro 40–444] in high yield and clearly proves that THL is attached via an ester bond and with retention of stereochemistry at all chiral centers to the side chain hydroxyl group of Ser‐152 of the lipase. The results obtained for human pancreatic lipase corroborate the inhibition mechanism of THL found on the porcine enzyme, and are in full agreement with the identification of the Ser‐152…His‐263…Asp‐176 catalytic triad in the X‐ray structure of human pancreatic lipase.

Piperidine-renin inhibitors compounds with improved physicochemical properties

Piperidine renin inhibitors with heterocyclic core modifications or hydrophilic attachments show improved physical properties (lower lipophilicity, improved solubility). Tetrahydroquinoline derivative rac-30 with a molecular weight of 517 and a log D(pH 7.4) of 1.9 displays potent and long lasting blood pressure lowering effects after oral administration to sodium depleted conscious marmosets.

De Novo design, synthesis, and in vitro evaluation of a new class of nonpeptidic inhibitors of the malarial enzyme plasmepsin II.

Malaria, a life-threatening disease caused by parasites of the genus Plasmodium, affects 500 million people annually, of which more than one million die. The emergence of multi-drugresistant strains of Plasmodium falciparum, the parasite that causes the deadliest form of malaria, exacerbates the situation and necessitates new medicines with novel modes of action. Plasmepsin II (PII ; EC3.4.23.39), a parasitic aspartic protease involved in the hemoglobin degradation process that takes place in an acidic vacuole, has been identified as a potential target for antimalarial therapy. Several groups reported PII inhibitors that mimic the natural substrate and display up to single-digit nanomolar activity. Inhibition of PII is expected to block the life cycle of the parasite. Here we report the synthesis and in vitro evaluation of a new class of nonpeptidic PII inhibitors developed with the help of structure-based de novo design that show up to single-digit micromolar inhibitory activities. A major conformational change around the active site of the human aspartic protease renin (EC3.4.23.15) upon complexation of 3,4-disubstituted piperidines has been observed, which unveils unexpected flexibility of the enzyme. The flap that lies over the catalytic dyad, and a tryptophan side chain of the core domain, move and thereby unlock a new hydrophobic pocket (flap pocket). The high sequence homology between renin and PII prompted us to hypothesize that an induced-fit adaptation such as that of the active site of renin might also be operative [3] H. Zhu, M. Bilgin, R. Bangham, D. Hall, A. Casamayor, P. Bertone, N. Lan, R. Jansen, S. Bidlingmaier, T. Houfek, T. Mitchell, P. Miller, R. A. Dean, M. Gerstein, M. Snyder, Science 2001, 293, 2101. [4] A.-C. Gavin, M. Bˆsche, R. Krause, P. Grandi, M. Marzioch, A. Bauer, J. Schultz, J. M. Rick, A.-M. Michon, C.-M. Cruciat, M. Remor, C. Hˆfert, M. Schelder, M. Brajenovic, H. Ruffner, A. Merino, K. Klein, M. Hudak, D. Dickson, T. Rudi, V. Gnau, A. Bauch, S. Bastuck, B. Huhse, C. Leutwein, M.-A. Heurtier, R. R. Copley, A. Edelmann, E. Querfurth, V. Rybin, G. Drewes, M. Raida, T. Bouwmeester, P. Bork, B. Seraphin, B. Kuster, G. Neubauer, G. Superti-Furga, Nature 2002, 415, 141. [5] M. Mann, R. C. Hendrickson, A. Pandey, Annu. Rev. Biochem. 2001, 70. [6] A. Dongre, J. K. Eng, J. R. Yates, Trends Biotechnol. 1997, 15, 418. [7] M. R. Wilkins, K. L. Williams, R. D. Appel, D. F. Hiochstrasser, Proteome Research: New Frontiers in Functional Genomics, Springer, Berlin, 1997. [8] Y. Ho, A. Gruhler, A. Heilbut, G. D. Bader, L. Moore, S.-L. Adams, A. Millar, P. Taylor, K. Bennett, K. Boutilier, L. Yang, C. Wolting, I. Donaldson, S. Schandorff, J. Shewnarane, M. Vo, J. Taggart, M. Goudreault, B. Muskat, C. Alfarano, D. Dewar, Z. Lin, K. Michalickova, A. R. Willems, H. Sassi, P. A. Nielsen, K. J. Rasmussen, J. R. Andersen, L. E. Johansen, L. H. Hansen, H. Jespersen, A. Podtelejnikov, E. Nielsen, J. Crawford, V. Poulsen, B. D. S ̆rensen, J. Matthiesen, R. C. Hendrickson, F. Gleeson, T. Pawson, M. F. Moran, D. Durocher, M. Mann, C. W. V. Hogue, D. Figeys, M. Tyers, Nature 2002, 415, 180. [9] L. Wang, A. Brock, B. Herberich, P. G. Schultz, Science 2001, 292, 498. [10] L. Wang, A. Brock, P. G. Schultz, J. Am. Chem. Soc. 2002, 124, 1836. [11] J. W. Chin, S. W. Santoro, A. B. Martin, D. S. King, L. Wang, P. G. Schultz, J. Am. Chem. Soc. 2002, 124, 9026. [12] J. C. Kauer, S. Erickson-Viitanen, H. R. Wolfe, W. F. DeGrado, J. Biol. Chem. 1986, 261, 10695. [13] J. W. Chin, A. B. Martin, D. S. King, L. Wang, P. G. Schultz, Proc. Natl. Acad. Sci. USA 2002, 99, 11020. [14] G. Dorman, G. D. Prestwich, Biochemistry 1994, 33, 5661. [15] D. A. Fancy, K. Melcher, S. A. Johnston, T. Kodadek, Chem. Biol. 1996, 3, 551. [16] Y. Maru, D. E. Afar, O. N. Witte, M. Shibuya, J. Biol. Chem. 1996, 271, 15353. [17] M. A. McTigue, D. R. Williams, J. A. Tainer, J. Mol. Biol. 1995, 246, 21. [18] W. A. Houry, D. Frishman, C. Eckerskorn, F. Lottspeich, F. U. Hartl, Nature 1999, 402, 147. [19] The near-UV irradiation per unit area (fluence) at 365 nm used in these studies for a five-minute exposure was approximately 10 ± 30 kJm . Classic studies on the effects of bacterial exposure at this wavelength have shown that lethal effects of such radiation on bacterial cells require fluences one to two orders of magnitude greater than this value. This observation raises the possibility that the phenotypes of live cells may be altered by photocrosslinking between protein surfaces in vivo. [20] B. Alberts, Cell 1998, 92, 291.

Design and Biological Evaluation of Novel, Balanced Dual PPARα/γ Agonists

An X‐ray‐guided design approach led to the identification of a novel, balanced class of α‐ethoxy‐phenylpropionic acid‐derived dual PPARα/γ agonists. The series shows a wide range of PPARα/γ ratios within a rather narrow structural space. Advanced compounds possess favorable physicochemical and pharmacokinetic profiles and show a high efficacy in T2D and dyslipidemia animal models.

Discovery of 4-Aryl-5,6,7,8-tetrahydroisoquinolines as Potent, Selective, and Orally Active Aldosterone Synthase (CYP11B2) Inhibitors: In Vivo Evaluation in Rodents and Cynomolgus Monkeys.

Inappropriately high levels of aldosterone are associated with many serious medical conditions, including renal and cardiac failure. A focused screen hit has been optimized into a potent and selective aldosterone synthase (CYP11B2) inhibitor with in vitro activity against rat, mouse, human, and cynomolgus monkey enzymes, showing a selectivity factor of 160 against cytochrome CYP11B1 in the last species. The novel tetrahydroisoquinoline compound (+)-(R)-6 selectively reduced aldosterone plasma levels in vivo in a dose-dependent manner in db/db mice and cynomolgus monkeys. The selectivity against CYP11B1 as predicted by cellular inhibition data and free plasma fraction translated well to Synacthen challenged cynomolgus monkeys up to a dose of 0.1 mg kg(-1). This compound, displaying good in vivo potency and selectivity in mice and monkeys, is ideally suited to perform mechanistic studies in relevant rodent models and to provide the information necessary for translation to non-human primates and ultimately to man.

Oxidosqualene Cyclase (OSC) Inhibitors for the Treatment of Dyslipidemia

Novel inhibitors of oxidosqualene cyclase (OSC) for the treatment of dyslipidemia are reported. Starting point for the chemistry program was a set of compounds derived from a fungicide project which, in addition to high affinity for OSC from Candida albicans, also showed high affinity for the human enzyme (hOSC). Here the evaluation process of different scaffolds is outlined for two representative series, the phenyl substituted benzo[d]isothiazoles and the aminocyclohexanes. The most promising compounds derived from the latter series were further profiled in vivo and showed promising properties with respect to modulation of lipid parameters.

Challenges and Rewards in Medicinal Chemistry Targeting Cardiovascular and Metabolic Diseases.

Medicinal chemistry has been transformed by major technological and conceptual innovations over the last three decades: structural biology and bioinformatics, structure and property based molecular design, the concepts of multidimensional optimization (MDO), in silico and experimental high-throughput molecular property analysis. The novel technologies advanced gradually and in synergy with biology and Roche has been at the forefront. Applications in drug discovery programs towards new medicines in cardiovascular and metabolic diseases are highlighted to show impact and advancement: the early discovery of endothelin antagonists for endothelial dysfunction (Bosentan), 11-beta hydroxysteroid dehydrogenase (11β-HSD1) inhibitors for dysregulated cellular glucocorticoid tonus (type 2 diabetes and metabolic syndrome) and non-covalent hormone sensitive lipase (HSL) inhibitors to study the scope of direct inhibition of lipolysis in the conceptual frame of lipotoxicity and type 2 diabetes.Medicinal chemistry has been transformed by major technological and conceptual innovations over the last three decades: structural biology and bioinformatics, structure and property based molecular design, the concepts of multidimensional optimization (MDO), in silico and experimental high-throughput molecular property analysis. The novel technologies advanced gradually and in synergy with biology and Roche has been at the forefront. Applications in drug discovery programs towards new medicines in cardiovascular and metabolic diseases are highlighted to show impact and advancement: the early discovery of endothelin antagonists for endothelial dysfunction (Bosentan), 11-beta hydroxysteroid dehydrogenase (11β-HSD1) inhibitors for dysregulated cellular glucocorticoid tonus (type 2 diabetes and metabolic syndrome) and non-covalent hormone sensitive lipase (HSL) inhibitors to study the scope of direct inhibition of lipolysis in the conceptual frame of lipotoxicity and type 2 diabetes.