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Your search keyword '"Goodman, KB"' showing total 3 results
Start Over Author "Goodman, KB" Journal journal of medicinal chemistry
3 results on '"Goodman, KB"'

1. Potent, selective and orally bioavailable dihydropyrimidine inhibitors of Rho kinase (ROCK1) as potential therapeutic agents for cardiovascular diseases.

Author

Sehon CA, Wang GZ, Viet AQ, Goodman KB, Dowdell SE, Elkins PA, Semus SF, Evans C, Jolivette LJ, Kirkpatrick RB, Dul E, Khandekar SS, Yi T, Wright LL, Smith GK, Behm DJ, Bentley R, Doe CP, Hu E, and Lee D

Subjects
Adenosine Triphosphate chemistry, Adenosine Triphosphate metabolism, Administration, Oral, Aldehydes chemistry, Animals, Crystallography, X-Ray, Indazoles chemistry, Models, Molecular, Molecular Structure, Protein Kinase Inhibitors administration & dosage, Pyrimidines administration & dosage, Rats, Structure-Activity Relationship, rho-Associated Kinases metabolism, Cardiovascular Diseases drug therapy, Cardiovascular Diseases enzymology, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors therapeutic use, Pyrimidines chemistry, Pyrimidines therapeutic use, rho-Associated Kinases antagonists & inhibitors
Abstract

Recent studies using known Rho-associated kinase isoform 1 (ROCK1) inhibitors along with cellular and molecular biology data have revealed a pivotal role of this enzyme in many aspects of cardiovascular function. Here we report a series of ROCK1 inhibitors which were originally derived from a dihydropyrimidinone core 1. Our efforts focused on the optimization of dihydropyrimidine 2, which resulted in the identification of a series of dihydropyrimidines with improved pharmacokinetics and P450 properties.

Published
2008
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2. Development of dihydropyridone indazole amides as selective Rho-kinase inhibitors.

Author

Goodman KB, Cui H, Dowdell SE, Gaitanopoulos DE, Ivy RL, Sehon CA, Stavenger RA, Wang GZ, Viet AQ, Xu W, Ye G, Semus SF, Evans C, Fries HE, Jolivette LJ, Kirkpatrick RB, Dul E, Khandekar SS, Yi T, Jung DK, Wright LL, Smith GK, Behm DJ, Bentley R, Doe CP, Hu E, and Lee D

Subjects
Amides pharmacokinetics, Amides pharmacology, Animals, Antihypertensive Agents pharmacokinetics, Antihypertensive Agents pharmacology, Aorta drug effects, Aorta physiology, Blood Pressure drug effects, In Vitro Techniques, Indazoles pharmacokinetics, Indazoles pharmacology, Intracellular Signaling Peptides and Proteins chemistry, Models, Molecular, Muscle Contraction drug effects, Muscle, Smooth, Vascular drug effects, Muscle, Smooth, Vascular physiology, Protein Serine-Threonine Kinases chemistry, Pyridones pharmacokinetics, Pyridones pharmacology, Pyrimidines chemical synthesis, Pyrimidines pharmacokinetics, Pyrimidines pharmacology, Rats, Rats, Inbred SHR, Structure-Activity Relationship, rho-Associated Kinases, Amides chemical synthesis, Antihypertensive Agents chemical synthesis, Indazoles chemical synthesis, Intracellular Signaling Peptides and Proteins antagonists & inhibitors, Protein Serine-Threonine Kinases antagonists & inhibitors, Pyridones chemical synthesis
Abstract

Rho kinase (ROCK1) mediates vascular smooth muscle contraction and is a potential target for the treatment of hypertension and related disorders. Indazole amide 3 was identified as a potent and selective ROCK1 inhibitor but possessed poor oral bioavailability. Optimization of this lead resulted in the discovery of a series of dihydropyridones, exemplified by 13, with improved pharmacokinetic parameters relative to the initial lead. Indazole substitution played a critical role in decreasing clearance and improving oral bioavailability.

Published
2007
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3. Discovery of aminofurazan-azabenzimidazoles as inhibitors of Rho-kinase with high kinase selectivity and antihypertensive activity.

Author

Stavenger RA, Cui H, Dowdell SE, Franz RG, Gaitanopoulos DE, Goodman KB, Hilfiker MA, Ivy RL, Leber JD, Marino JP Jr, Oh HJ, Viet AQ, Xu W, Ye G, Zhang D, Zhao Y, Jolivette LJ, Head MS, Semus SF, Elkins PA, Kirkpatrick RB, Dul E, Khandekar SS, Yi T, Jung DK, Wright LL, Smith GK, Behm DJ, Doe CP, Bentley R, Chen ZX, Hu E, and Lee D

Subjects
Animals, Antihypertensive Agents pharmacokinetics, Antihypertensive Agents pharmacology, Aorta drug effects, Aorta physiology, Benzimidazoles pharmacokinetics, Benzimidazoles pharmacology, Blood Pressure drug effects, In Vitro Techniques, Models, Molecular, Muscle Contraction drug effects, Muscle, Smooth, Vascular drug effects, Muscle, Smooth, Vascular physiology, Oxadiazoles pharmacokinetics, Oxadiazoles pharmacology, Rats, Rats, Inbred SHR, Structure-Activity Relationship, rho-Associated Kinases, Antihypertensive Agents chemical synthesis, Benzimidazoles chemical synthesis, Intracellular Signaling Peptides and Proteins antagonists & inhibitors, Oxadiazoles chemical synthesis, Protein Serine-Threonine Kinases antagonists & inhibitors
Abstract

The discovery, proposed binding mode, and optimization of a novel class of Rho-kinase inhibitors are presented. Appropriate substitution on the 6-position of the azabenzimidazole core provided subnanomolar enzyme potency in vitro while dramatically improving selectivity over a panel of other kinases. Pharmacokinetic data was obtained for the most potent and selective examples and one (6n) has been shown to lower blood pressure in a rat model of hypertension.

Published
2007
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