Jerome Cohen

Abbott Fund

Author Statistics

Papers

Citation

H-Index

i-10 index

Research Trends

Author Order

Document Type

Co-Authors

Herman H. Stein

Centro Universitário Fundação Assis Gurgacz

Saul H. Rosenberg

AbbVie (United States)

Hing L. Sham

British Columbia Children's Hospital

Jacob J. Plattner

United States Army Medical Research Institute of Infectious Diseases

Hollis D. Kleinert

Abbott (United States)

William R. Baker

Northern Illinois University

Wen‐Zhen Gu

Sun Yat-sen University

Kennan C. Marsh

AbbVie (United States)

Ed de Lara

Abbott (United Kingdom)

Keith W. Woods

Clark Atlanta University

Cooperative Institutions

Abbott Fund

Abbott (United States)

Abbott (United Kingdom)

AbbVie (United States)

Moffitt Cancer Center

University of South Florida

Discovery Laboratories (United States)

In-Q-Tel

The University of Texas at Austin

Australian National University

Author Statistics

Papers

Citation

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i-10 index

Research Field

Discovery of a Peptide-Based Renin Inhibitor with Oral Bioavailability and Efficacy

Science (1992)

Hollis D. Kleinert Saul H. Rosenberg William R. Baker Herman H. Stein Vered Klinghofer

Peptidic renin inhibitors have been poorly absorbed across the intestine or rapidly eliminated by the liver and have been reported to have oral bioavailabilities of less than 2%. A peptide-based renin inhibitor, A-72517 (molecular mass of 706 daltons), was devised that has oral bioavailabilities of 8, 24, 32, and 53% in the monkey, rat, ferret, and dog, respectively. Dose-related reductions in blood pressure, plasma renin activity, and plasma angiotensin II in parallel with increased plasma drug concentrations were observed after oral administration of A-72517 to conscious, salt-depleted dogs. Thus, peptide-based molecules of sizable molecular mass can be absorbed intact into the systemic circulation of animals. These findings support the potential of peptide-based drugs for oral administration.

Renin inhibitor

Plasma renin activity

Systemic circulation

10.1126/science.1411510

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Citations (109)

Novel non-basic bioisostere of histidine synthesized from L-aspartic acid

Journal of the Chemical Society Chemical Communications (1987)

Hing L. Sham Herman H. Stein Jerome Cohen

H. L. Sham, H. Stein and J. Cohen, J. Chem. Soc., Chem. Commun., 1987, 1792 DOI: 10.1039/C39870001792

Bioisostere

Aspartic acid

10.1039/c39870001792

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Citations (6)

The measurement by a microtitration technique of carbon dioxide production in rat brain slices. Studies with glucose, fructose, and xylitol

Analytical Biochemistry (1976)

Herman H. Stein Jerome Cohen

10.1016/s0003-2697(76)80010-3

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Citations (3)

Novel and selective imidazole-containing biphenyl inhibitors of protein farnesyltransferase

Bioorganic & Medicinal Chemistry Letters (2003)

Michael L. Curtin Alan S. Florjancic Jerome Cohen Wen‐Zhen Gu David J. Frost

Imidazole

Farnesyltransferase inhibitor

Biphenyl

10.1016/s0960-894x(03)00096-9

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Citations (16)

Electroencephalography

Access Science (2015)

Jerome Cohen

AccessScience is an authoritative and dynamic online resource that contains incisively written, high-quality educational material covering all major scientific disciplines. An acclaimed gateway to scientific knowledge, AccessScience is continually expanding the ways it can demonstrate and explain core, trustworthy scientific information that inspires and guides users to deeper knowledge.

Trustworthiness

Gateway (web page)

10.1036/1097-8542.221300

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Citations (0)

Slow, tight binding to human renin of some nonpeptidic renin inhibitors containing a 4‐methoxymethoxypiperidinylamide at the P4 position

FEBS Letters (1992)

Herman H. Stein Anthony K. L. Fung Jerome Cohen William R. Baker Saul H. Rosenberg

A series of nonpeptidic human renin inhibitors with a 4-methoxymethoxypiperidinylamide at the P4 position of the molecule exhibited slow tight binding to the enzyme. Replacement of the methoxymethoxy moiety on the piperidine ring with H, OH, methoxyethyl, propyloxy or n-butyl eliminated the effect. The inhibition was partially reversed by prolonged dialysis at 4 degrees C, arguing against formation of a covalent bond in the tightened complex.

Position (finance)

10.1016/0014-5793(92)80867-g

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Citations (10)

New inhibitors of renin that contain novel phosphostatine Leu-Val replacements

Journal of Medicinal Chemistry (1990)

Joseph F. Dellaria Robert G. Maki Herman H. Stein Jerome Cohen David N. Whittern

A novel series of renin inhibitors based on the Phe8-His9-Leu10-Val11 substructure of renin's natural substrate, angiotensinogen, is reported. These inhibitors retain the Phe8-His9 portion of the native substructure and employ novel phosphostatine Leu10-Val11 replacements (LVRs). The phosphostatine LVRs were prepared by condensing a dialkyl phosphonate ester stabilized anion with either N-t-Boc-amino aldehydes or N-tritylamino aldehydes (derived from the corresponding amino acid). Structure-activity relationships at the Leu10 side chain revealed that the LVR derived from L-cyclohexylalanine provided a 130-fold boost in potency over the LVR derived from L-leucine. The dialkyl ester moiety was varied and a loss in potency was incurred when the alkyl ester was chain extended or alpha-branched; dimethyl esters provided optimum potency. The phosphonate moiety was replaced by a half-acid half-ester phosphonate and dimethylphosphinate; both replacements lead to a loss in potency. The more potent inhibitors (IC50 = 20-50 nM) were found to be selective inhibitors for renin over porcine pepsin and bovine cathepsin D (little or no inhibition was observed at 10(-5) M).

Moiety

Phosphonate

Structure–activity relationship

10.1021/jm00164a011

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Citations (100)

Synthesis of 6(S)-amino-7-cyclohexyl-4,4-difluoro-3(R),5(R)-dihydroxy-2-methyiheptane, a novel dipeptide mimic

Journal of the Chemical Society Chemical Communications (1990)

Hing L. Sham Cheryl A. Rempel Herman H. Stein Jerome Cohen

H. L. Sham, C. A. Rempel, H. Stein and J. Cohen, J. Chem. Soc., Chem. Commun., 1990, 904 DOI: 10.1039/C39900000904

Sequence (biology)

10.1039/c39900000904

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Citations (15)

Studies directed toward the design of orally active renin inhibitors. 1. Some factors influencing the absorption of small peptides

Journal of Medicinal Chemistry (1993)

Saul H. Rosenberg Kenneth P. Spina Keith W. Woods Jim Polakowski Donald L. Martin

A systematic evaluation of structure-absorption relationships using a high throughput intraduodenal rat screening model has led to the delineation of a set of structural parameters that appear to govern bioavailability in a series of peptide-based renin inhibitors. Optimum structures, exemplified by 25 and 41, incorporated a single, solubilizing substituent at the C- or N-terminus combined with a lipophilic P2-site residue. Both inhibitors gave unprecedented plasma drug levels upon intraduodenal administration to monkeys, and the calculated bioavailability for 41 (14 +/- 4%) is the highest reported for any peptidic renin inhibitor.

10.1021/jm00056a005

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Citations (54)

Optimization and in vivo evaluations of a series of small, potent, and specific renin inhibitors containing a novel Leu-Val replacement

Journal of Medicinal Chemistry (1987)

Joseph F. Dellaria Robert G. Maki Barbara A. Bopp Jerome Cohen Hollis D. Kleinert

Further structure-activity relationships (SAR) for a novel dipeptide series inhibitors are reported. These inhibitors retain the Phe8-His9 portion of angiotensinogen and employ a unique Leu10-Val11 replacement [(LVR), ref 2]. SAR at the Leu10 side chain revealed that the LVR derived from cyclohexylalanine provided a nearly 10-fold boost in potency for the final inhibitor. In addition SAR work was carried out to delineate the relationships between binding potency and (1) the size, shape, and charge of the side chain at the His9 position; (2) the size and topology of the side chain at the Phe8 site; and (3) the size of the Phe8 N-protecting group. One of the more potent inhibitors, 12, was shown to provide a substantial antihypertensive effect in a sodium depleted monkey model when administered intravenously. Metabolism work, in Sprague-Dawley rats, provided insights into the susceptibility of 12 to significant hepatic clearance and provided encouraging evidence for intestinal absorption.

Structure–activity relationship

Side chain

10.1021/jm00394a035

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Citations (34)