Jochen Knolle

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Anna Dornhaus

University of Arizona

Kristen J Gremillion

Ohio State University

Mark Collard

Simon Fraser University

Bronwyn Hall

University of California, Berkeley

Kevin Arbuckle

Swansea University

Jyotica Batra

Mayo Clinic

Mohammad Hossein Karimi-Jafari

University of Tehran

Haris Saslis-Lagoudakis

Royal Botanic Gardens Kew

Prof. Raymond R Tjandrawinata, PhD, MS, MBA, FRSC, FRSPH

Atma Jaya Catholic University of Indonesia

امال محمود

University of Sadat City

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Papers by Jochen Knolle

Acylguanidine derivatives as inhibitors of bone resorption and as vitronectin receptor antagonists

by Sarah Bodary and Jochen Knolle

Blocking the bradykinin response: Pharmacodynamics and safety of icatibant, a potent and selective bradykinin B2 receptor antagonist

Molecular Immunology, 2008

Icatibant has no impact on renal function in healthy subjects

Clinical Pharmacology & Therapeutics, 2004

The role of bradykinin (BK) in renal regulations is still controversial. To elucidate whether Ica... more The role of bradykinin (BK) in renal regulations is still controversial. To elucidate whether Icatibant, a potent BK antagonist on B2 receptors, can interfere with renal function under normal conditions, we performed sinistrin and para-aminohippurate (PAH) clearances, plasma levels and excretion rate of electrolytes, albumin, urate, endogenous lithium, as well as plasma renin, aldosterone and endothelin in 14 healthy males under Icatibant infusion.Part I (2 panels of 4 subjects) compared single 4h infusions (0.005 to 0.8 mg/kg) in ascending, double-blind, placebo-controlled design. Part II tested renal function on the 3rd day of a 72h Icatibant or placebo infusion, in a 2-way crossover, double blind design.No changes in glomerular filtration rate (sinistrin), renal blood flow (PAH), or in proximal renal tubular function (lithium and urate clearances) were detected. Sodium, potassium and chloride excretions, micro-albuminuria, urinary volume, and hematocrit remained unchanged. Vital signs (supine and orthostatic blood pressure, heart rate), body weight, and hormone concentrations were also unaltered. The safety and tolerability of Icatibant was excellent. This study had enough power to detect physiologically significant effects but not even trends for changes in renal function could be suspected.In conclusion, these results strongly advocate against a physiological role of BK in the regulation of renal function under normal conditions.

Synthesis and application of acid labile anchor groups for the synthesis of peptide amides by Fmoc-solid-phase peptide synthesis

International journal of peptide and protein research, 1989

The preparation and application of a new linker for the synthesis of peptide amides using a modif... more The preparation and application of a new linker for the synthesis of peptide amides using a modified Fmoc-method is described. The new anchor group was developed based on our experience with 4,4'-dimethoxybenzhydryl (Mbh)-protecting group for amides. Lability towards acid treatment was increased dramatically and results in an easy cleavage procedure for the preparation of peptide amides. The synthesis of N-9-fluorenylmethoxycarbonyl- ([5-carboxylatoethyl-2.4-dimethoxyphenyl)- 4'-methoxyphenyl]-methylamin is reported in detail. This linker was coupled to a commercially available aminomethyl polystyrene resin. Peptide synthesis proceeded smoothly using HOOBt esters of Fmoc-amino acids. Release of the peptide amide and final cleavage of the side chain protecting groups was accomplished by treatment with trifluoroacetic acid-dichloromethane mixtures in the presence of scavengers. The synthesis of peptide amides such as LHRH and C-terminal hexapeptide of secretin are given as exa...

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Synthesis of peptide amides by Fmoc-solid-phase peptide synthesis and acid labile anchor groups

International journal of peptide and protein research, 1989

The preparation and use of new anchor groups for the synthesis of peptide amides by solid-phase p... more The preparation and use of new anchor groups for the synthesis of peptide amides by solid-phase peptide synthesis employing the Fmoc-method is described. Based on the structure of the 4,4'-dimethoxybenzhydryl group (Mbh) handles were developed, which could be cleaved by mild acid treatment to give carboxamides. The syntheses and application of Fmoc-amino-acid-(4-carboxylatomethyloxyphenyl-4'-methoxyphenyl) methyl amide and Fmoc-(4-carboxylatopropyloxyphenyl-4'-methoxyphenyl) methyl amide are described in detail. These handles were coupled to resins and a stepwise elongation of peptide chains proceeded smoothly with N alpha-9-fluorenylmethoxycarbonyl (Fmoc) amino acid derivatives using a carbodiimide/HOBt mediated reaction. The final cleavage of side-chain protecting groups and the release of the C-terminal amide moiety was achieved by the treatment with trifluoroacetic acid, dichloromethane in the presence of scavengers. Various peptides, such as the Leu-enkephalin amide...

Proof-of-concept study of icatibant (JE 049), a bradykinin B2 receptor antagonist in treatment of hereditary angioedema

Clinical Pharmacology & Therapeutics, 2005

Background/Aims: Bradykinin (BK) is considered to be a key mediator in acute attacks of hereditar... more Background/Aims: Bradykinin (BK) is considered to be a key mediator in acute attacks of hereditary angioedema (HAE) due to C1 inhibitor (C1-INH) deficiency. During acute HAE attacks, increased BK plasma levels are detectable. The highly specific BK B2 receptor antagonist Icatibant leads to reduction of fluid extravasation in C1-INH knockout mice. The efficacy and safety of Icatibant in the treatment

Facile SPS of peptides having C-terminal Asn and Gln*

International Journal of Peptide and Protein Research, 1990

Attachment of Fmoc-asparagine or glutamine to p-alkoxybenzyl alcohol type resins has always been ... more Attachment of Fmoc-asparagine or glutamine to p-alkoxybenzyl alcohol type resins has always been difficult and not very effective. A very simple and effective method for the preparation of peptides terminating in asparagine or glutamine is described. The method involves quantitative attachment of Fmoc-Asp-OtBu or Fmoc-Glu-OtBu via their side-chain carboxyl group to a resin functionalized with our TMBPA linker for peptide amides. Peptide synthesis is performed using our standard Fmoc chemistry, and treatment with acid, e.g. TFA/DCM/scavenger mixtures, releases the Asn or Gln peptides.

The bradykinin antagonist icatibant increases electrolyte and water excretion after sodium challenge in patients with liver cirrhosis

Clinical Pharmacology & Therapeutics - CLIN PHARMACOL THER, 2004

Purpose: Patients with hepatic insufficiency are known to cope less efficiently with Na load. In ... more Purpose: Patients with hepatic insufficiency are known to cope less efficiently with Na load. In a rat CCl4-induced liver cirrhosis model, Icatibant, a potent bradykinin-2 receptor antagonist, prevented Na retention, improved diuresis, and reduced microvascular leakage (Wirth et al Eur J Pharmacol 1997; 37: 45-53). Methods: In a randomized, double-blind, proof-of-concept study, 8 patients with liver cirrhosis (Child Pugh score 5-8) and 8 healthy subjects on standardized diet received a constant 3 day infusion of Icatibant (0.15 mg/kg/day) or vehicle (placebo), with Na load on Day 2 (2L NaCl 0.9% i.v.). Results: Using sinistrine clearance, renal function did not change during treatment while the baseline extracellular body water (Vd) was higher in patients than volunteers (12.4 vs. 10.2 L/m2, p=0.05). In patients, 6-12h after NaCl load, Icatibant increased Na excretion vs. placebo by 6.9 mmol/h (p=0.02), K excretion by 1.24 mmol/h (p=0.04), urine osmolarity by 18.54 mmol/h (p=0.01), ...

The synthesis of polyamide nucleic acids using a novel monomethoxytrityl protecting-group strategy

Tetrahedron, 1995

The preparation of 9-Fluorenylmethoxycarbonyl(Fmoc) protected building blocks for the synthesis o... more The preparation of 9-Fluorenylmethoxycarbonyl(Fmoc) protected building blocks for the synthesis of polyamide nucleic acids (PNAs) is described. Use of 4-Methoxyphenyldiphenylmethyl (Mmt)-protecting groups for the exocyclic amino function of the nucleobases enhances the solubility of the monomers and allows final deprotection by mild acid treatment. The novel synthetic route is exemplified by the synthesis of heptameric and octameric PNAs.

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Icatibant, a New Bradykinin-Receptor Antagonist, in Hereditary Angioedema

New England Journal of Medicine, 2010

Hereditary angioedema is characterized by recurrent attacks of angioedema of the skin, larynx, an... more

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Discovery of an Orally Active Non-Peptide Fibrinogen Receptor Antagonist Based on the Hydantoin Scaffold

Journal of Medicinal Chemistry, 2001

Antagonists of the platelet fibrinogen receptor (GP IIb/IIIa receptor) are expected to be a promi... more Antagonists of the platelet fibrinogen receptor (GP IIb/IIIa receptor) are expected to be a promising new class of antithrombotic agents. The binding of fibrinogen to the fibrinogen receptor depends on an Arg-Gly-Asp-Ser (RGDS) tetrapeptide recognition motif. Structural modifications of the RGDS lead have led to the discovery of a non-peptide RGD mimetic GP IIb/IIIa antagonist 44 (S 1197). Compound 44 inhibited, in a dose dependent and reversible manner, human and dog platelet aggregation as well as 125I-fibrinogen binding to ADP-activated human gel filtered platelets and isolated GP IIb/IIIa with K(i) values of 9 nM and 0.17 nM, respectively. A pharmacophore mapping procedure with QXP and a 3D-QSAR analysis applying the GRID/GOLPE methodology yielded a stable, rather predictive model and revealed structural features which are important for binding. Hydrophobic substitutions both at the hydantoin nucleus and at the C-terminus increase the affinity toward the fibrinogen receptor. The crystalline ethyl ester prodrug 48 (HMR 1794) is an orally active antithrombotic agent which is a promising drug candidate for the treatment of thrombotic diseases in humans.

Atrial natriuretic factor protects the isolated working ischaemic rat heart against the action of angiotensin II

Journal of Hypertension, 1988

The interaction between atrial natriuretic factor [synthetic human ANF-(103-126)] and angiotensin... more The interaction between atrial natriuretic factor [synthetic human ANF-(103-126)] and angiotensin II (Ang II) and its influence on reperfusion arrhythmias, cardiodynamics, enzyme loss and metabolic changes were investigated in isolated ischaemic working rat hearts. Acute regional myocardial ischaemia was induced by coronary artery occlusion which was associated with ventricular fibrillation. Perfusion with 1 X 10(-9) mol/l Ang II markedly aggravated these arrhythmias. Perfusion with 1 X 10(-7) mol/l ANF, in contrast, gave protection against ventricular fibrillation and prevented Ang II-induced aggravation of ventricular fibrillation. Atrial natriuretic factor improved cardiodynamics, in particular, during reperfusion, whereas Ang II impaired cardiodynamics and increased the release of creatine kinase and lactate dehydrogenase. These adverse effects of Ang II were absent when ANF was simultaneously perfused. Compared with control hearts, myocardial tissue levels of glycogen, ATP and creatine phosphate were increased in hearts perfused with either ANF or ANF plus Ang II, whereas lactate levels decreased. Perfusion with Ang II alone led to deterioration in these metabolic parameters. These results in isolated working rat hearts suggest that ANF protects against the consequences of ischaemia and reperfusion and that functional antagonism between ANF and Ang II may contribute to this.

Treatment Of Acute Edema Attacks In Hereditary Angioedema With A Bradykinin Receptor-2 Antagonist (Icatibant)

Journal of Allergy and Clinical Immunology, 2007

Absolute Bioavailability of Subcutaneously Administered Icatibant, a Selective and Potent Bradykinin B2 Receptor Antagonist

Journal of Allergy and Clinical Immunology, 2007

DesArg9D-Arg[Hyp3,Thi5,D-Tic7,Oic8]bradykinin (desArg10-[Hoe140]) is a bradykinin B1 receptor antagonist

European Journal of Pharmacology, 1991

Dcs~g~-~-~~Hyp3,This,D-Tic',0ic~]BK is a potent and stable B, bradykinin (BK) receptor antagonist... more Dcs~g~-~-~~Hyp3,This,D-Tic',0ic~]BK is a potent and stable B, bradykinin (BK) receptor antagonist which was one order of magnitude more potent (ICs,, 1.2 X lo-' Ml in the isolated rabbit aorta than the known selective B, BK receptor antagonist, desArgg-[Leu']BK (ICj,, 1.1 X lo-' M). DesArg"-D-Arg[Hyp",Thi',D-Tic',Oic']BK is the desArg"' derivative of Hoel40, a new, potent, stable, selective and long-acting BI BK receptor antagonist. In El2 organ preparation it was three orders of magnitude less potent than Hoel40. Since it is potent and stable it could contribute to the investigation of B, BK receptor function. dcsArg"-D-ArdHyp",Thi',D-Tic',Oic']bradykinin; Hoel4O; Bradykinin receptor antagonists; Bradykinin B, receptors; Bradykinin Bz receptors 1. IWoduction

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Oral Eosinophilic Ulcer, an Epstein-Barr Virus-Associated CD30+ Lymphoproliferation?

Dermatology, 2011

Eosinophilic ulcer of the oral mucosa is a benign lesion of unclear pathogenesis mostly affecting... more Eosinophilic ulcer of the oral mucosa is a benign lesion of unclear pathogenesis mostly affecting the tongue. It has been suggested to represent a reactive pattern to several stimuli. We report on a 12-year-old boy who presented with a painless infiltrating ulcer on the gingiva of the lower jaw, which was covered by necrotic yellowish slough. There were no pathologic features of the jawbones or regional lymph nodes. Histopathological, immunohistochemical and gene rearrangement studies were in agreement with eosinophilic ulcer with predominant oligoclonal CD3+ and CD30+ T lymphocytes expressing the Epstein-Barr virus membrane protein. The ulcer resolved within 4 weeks and follow-up for 3 years revealed no evidence of recurrence. Epstein-Barr virus may have played a role in triggering this reactive lymphoproliferative disorder.

Peptidomimetic C5a receptor antagonists with hydrophobic substitutions at the C-terminus: Increased receptor specificity and in vivo activity

Bioorganic & Medicinal Chemistry Letters, 2006

A new class of peptidomimetic C5a receptor antagonists characterized by C-terminal amino acids wi... more A new class of peptidomimetic C5a receptor antagonists characterized by C-terminal amino acids with hydrophobic side chains is presented. Systematic optimization of the first hits led to JPE1375 (36), which was intensively characterized in vitro and in vivo. Compound 36 exhibits high microsomal stability and receptor specificity and is highly active in an immune complex mediated peritonitis model (reverse passive Arthus reaction) in mice.

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Synthesis of polyamide nucleic acids (PNAs) using a novel Fmoc/Mmt protecting-group combination

Bioorganic & Medicinal Chemistry Letters, 1996

12. Data for the compounds are given below as follows: yield (%)/ R f -values on Merck DC Kieselg... more

RGD Mimetics containing a central hydantoin scaffold: αVβ3 vs αIIbβ3 selectivity requirements

Bioorganic & Medicinal Chemistry Letters, 2000

AbstractÐThe synthesis of a series of RGD mimetic a V b 3 antagonists containing a hydantoin scao... more AbstractÐThe synthesis of a series of RGD mimetic a V b 3 antagonists containing a hydantoin scaold is shown. The results demonstrate some of the structural requirements for the design of selective a V b 3 antagonists (vs a IIb b 3 ) in terms of the Arg-mimetic, the distance between N-and C-terminus and the lipophilic side chain. #

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HIV protease inhibitor HOE/BAY 793, structure-activity relationships in a series of C2-symmetric diols

Bioorganic & Medicinal Chemistry, 1995

A detailed structure-activity relationship of Ca-symmetric diol inhibitors of HIV-1 protease lead... more A detailed structure-activity relationship of Ca-symmetric diol inhibitors of HIV-1 protease leads to inhibitor 6 (HOE/BAY 793) which is outstanding in the inhibition of the enzyme and in the inhibition of viral replication in HIV infected cell culture (ICso: 0.3 riM; ECso: 3 nM). There are well defined steric requirements for the design of the side chains P1-P3 of the inhibitors. In addition, all three side chains need to be lipophilic. While the enzyme tolerates hydrophilic substituents in some cases, drastic reductions in anti-HIV activity are observed in cell culture, most likely due to insufficient cell penetration.

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Acylguanidine derivatives as inhibitors of bone resorption and as vitronectin receptor antagonists

by Sarah Bodary and Jochen Knolle

Blocking the bradykinin response: Pharmacodynamics and safety of icatibant, a potent and selective bradykinin B2 receptor antagonist

Molecular Immunology, 2008

Icatibant has no impact on renal function in healthy subjects

Clinical Pharmacology & Therapeutics, 2004

Synthesis and application of acid labile anchor groups for the synthesis of peptide amides by Fmoc-solid-phase peptide synthesis

International journal of peptide and protein research, 1989

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Synthesis of peptide amides by Fmoc-solid-phase peptide synthesis and acid labile anchor groups

International journal of peptide and protein research, 1989

Proof-of-concept study of icatibant (JE 049), a bradykinin B2 receptor antagonist in treatment of hereditary angioedema

Clinical Pharmacology & Therapeutics, 2005

Facile SPS of peptides having C-terminal Asn and Gln*

International Journal of Peptide and Protein Research, 1990

The bradykinin antagonist icatibant increases electrolyte and water excretion after sodium challenge in patients with liver cirrhosis

Clinical Pharmacology & Therapeutics - CLIN PHARMACOL THER, 2004

The synthesis of polyamide nucleic acids using a novel monomethoxytrityl protecting-group strategy

Tetrahedron, 1995

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Icatibant, a New Bradykinin-Receptor Antagonist, in Hereditary Angioedema

New England Journal of Medicine, 2010

Hereditary angioedema is characterized by recurrent attacks of angioedema of the skin, larynx, an... more

Download

Discovery of an Orally Active Non-Peptide Fibrinogen Receptor Antagonist Based on the Hydantoin Scaffold

Journal of Medicinal Chemistry, 2001

Atrial natriuretic factor protects the isolated working ischaemic rat heart against the action of angiotensin II

Journal of Hypertension, 1988

Treatment Of Acute Edema Attacks In Hereditary Angioedema With A Bradykinin Receptor-2 Antagonist (Icatibant)

Journal of Allergy and Clinical Immunology, 2007

Absolute Bioavailability of Subcutaneously Administered Icatibant, a Selective and Potent Bradykinin B2 Receptor Antagonist

Journal of Allergy and Clinical Immunology, 2007

DesArg9D-Arg[Hyp3,Thi5,D-Tic7,Oic8]bradykinin (desArg10-[Hoe140]) is a bradykinin B1 receptor antagonist

European Journal of Pharmacology, 1991

Download

Oral Eosinophilic Ulcer, an Epstein-Barr Virus-Associated CD30+ Lymphoproliferation?

Dermatology, 2011

Peptidomimetic C5a receptor antagonists with hydrophobic substitutions at the C-terminus: Increased receptor specificity and in vivo activity

Bioorganic & Medicinal Chemistry Letters, 2006

Download

Synthesis of polyamide nucleic acids (PNAs) using a novel Fmoc/Mmt protecting-group combination

Bioorganic & Medicinal Chemistry Letters, 1996

12. Data for the compounds are given below as follows: yield (%)/ R f -values on Merck DC Kieselg... more

RGD Mimetics containing a central hydantoin scaffold: αVβ3 vs αIIbβ3 selectivity requirements

Bioorganic & Medicinal Chemistry Letters, 2000

Download

HIV protease inhibitor HOE/BAY 793, structure-activity relationships in a series of C2-symmetric diols

Bioorganic & Medicinal Chemistry, 1995

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