Development of dihydropyridone indazole amides as selective Rho-kinase inhibitors.
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.
Goodman
Krista B
KB
Department of Medicinal Chemistry, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA. krista.b.goodman@gsk.com
Cui
Haifeng
H
Dowdell
Sarah E
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Gaitanopoulos
Dimitri E
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Ivy
Robert L
RL
Sehon
Clark A
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Stavenger
Robert A
RA
Wang
Gren Z
GZ
Viet
Andrew Q
AQ
Xu
Weiwei
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Ye
Guosen
G
Semus
Simon F
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Evans
Christopher
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Fries
Harvey E
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Jolivette
Larry J
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Kirkpatrick
Robert B
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Dul
Edward
E
Khandekar
Sanjay S
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Yi
Tracey
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Jung
David K
DK
Wright
Lois L
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Smith
Gary K
GK
Behm
David J
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Bentley
Ross
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Doe
Christopher P
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Hu
Erding
E
Lee
Dennis
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D000577:Amides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects; D066298:In Vitro Techniques; D007191:Indazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011728:Pyridones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D013329:Structure-Activity Relationship; D054460:rho-Associated Kinases
D000577:Amides; D000959:Antihypertensive Agents; D007191:Indazoles; D047908:Intracellular Signaling Peptides and Proteins; D011728:Pyridones; D011743:Pyrimidines; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases