Structure-activity relationships, and drug metabolism and pharmacokinetic properties for indazole piperazine and indazole piperidine inhibitors of ROCK-II.
ROCK has been implicated in many diseases ranging from glaucoma to spinal cord injury and is therefore an important target for therapeutic intervention. In this study, we have designed a series of 1-(4-(1H-indazol-5-yl)piperazin-1-yl)-2-hydroxy(or 2-amino) analogs and a series of 1-(4-(1H-indazol-5-yl amino)piperidin-1-yl)-2-hydroxy(or 2-amino) inhibitors of ROCK-II. SR-1459 has IC(50)=13nM versus ROCK-II while the IC(50)s for SR-715 and SR-899 are 80nM and 100nM, respectively. Many of these inhibitors, especially the 2-amino substituted analogs for both series, are modest/potent CYP3A4 inhibitors as well. However, a few of these inhibitors (SR-715 and SR-899) show strong selectivity for ROCK-II over CYP3A4, but the overall potency of the 2-amino analogs (SR-1459) on CYP3A4 and the high clearance and volume of distribution of these compounds makes the in vivo utility of these analogs undesirable.
Feng
Yangbo
Y
Department of Biochemistry and Department of Drug Discovery, The Scripps Research Institute, 5353 Parkside Drive, RF-2 Jupiter, FL 33458, USA.
Cameron
Michael D
MD
Frackowiak
Bozena
B
Griffin
Evelyn
E
Lin
Li
L
Ruiz
Claudia
C
Schröter
Thomas
T
LoGrasso
Philip
P
D000818:Animals; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004355:Drug Stability; D006801:Humans; D007191:Indazoles / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics*; D020128:Inhibitory Concentration 50; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D004364:Pharmaceutical Preparations / Q000378:metabolism; D010599:Pharmacokinetics; D010879:Piperazines / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D010880:Piperidines / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D013329:Structure-Activity Relationship; D054460:rho-Associated Kinases
D065607:Cytochrome P-450 Enzyme Inhibitors; D007191:Indazoles; D047908:Intracellular Signaling Peptides and Proteins; D004364:Pharmaceutical Preparations; D010879:Piperazines; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases