Solving time-dependent CYP3A4 inhibition for a series of indole-phenylacetic acid dual antagonists of the PGD(2) receptors CRTH2 and DP.
Based on their structural similarity to previously described compound AMG 009, indole-phenyl acetic acids were proposed to be potent dual inhibitors of chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2 or DP2) and prostanoid D receptor (DP or DP1). This series was equipotent to AMG 009 in binding assays against both receptors but exhibited decreased serum shift. We discovered early in the optimization of these indole-phenylacetic acid compounds that they demonstrated CYP3A4 time-dependent inhibition (TDI). Hypothesizing that the source of TDI was the indole core we modified the 1,2,3-substitution to eventually afford a highly potent modulator of CRTH2 and DP which did not exhibit TDI.
Department of Therapeutic Discovery, Amgen, Inc., 1120 Veterans Blvd, South San Francisco, CA 94080, USA. Electronic address: mgjohnso@amgen.com.
Michael G
MG
Johnson
Department of Therapeutic Discovery, Amgen, Inc., 1120 Veterans Blvd, South San Francisco, CA 94080, USA.
Jim Jiwen
JJ
Liu
Department of Therapeutic Discovery, Amgen, Inc., 1120 Veterans Blvd, South San Francisco, CA 94080, USA.
An-Rong
AR
Li
Department of Therapeutic Discovery, Amgen, Inc., 1120 Veterans Blvd, South San Francisco, CA 94080, USA.
Bettina
B
van Lengerich
Department of Therapeutic Discovery, Amgen, Inc., 1120 Veterans Blvd, South San Francisco, CA 94080, USA.
Sophie
S
Wang
Department of Therapeutic Discovery, Amgen, Inc., 1120 Veterans Blvd, South San Francisco, CA 94080, USA.
Julio C
JC
Medina
Department of Inflammation Research, Amgen, Inc., 1201 Amgen Court West, Seattle, WA 98119, USA.
Tassie L
TL
Collins
Department of Inflammation Research, Amgen, Inc., 1201 Amgen Court West, Seattle, WA 98119, USA.
Jay
J
Danao
Department of Inflammation Research, Amgen, Inc., 1201 Amgen Court West, Seattle, WA 98119, USA.
Lisa
L
Seitz
Department of Inflammation Research, Amgen, Inc., 1201 Amgen Court West, Seattle, WA 98119, USA.
Angela
A
Willee
Department of Inflammation Research, Amgen, Inc., 1201 Amgen Court West, Seattle, WA 98119, USA.
Warren
W
D'Souza
Department of Inflammation Research, Amgen, Inc., 1201 Amgen Court West, Seattle, WA 98119, USA.
Alison L
AL
Budelsky
Department of Pharmacokinetics, Metabolism and Distribution, Amgen, Inc., 1120 Veterans Blvd, South San Francisco, CA 94080, USA.
Peter W
PW
Fan
Department of Pharmacokinetics, Metabolism and Distribution, Amgen, Inc., 1120 Veterans Blvd, South San Francisco, CA 94080, USA.
Simon G W
SG
Wong
D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D010648:Phenylacetates / Q000737:chemistry / Q000494:pharmacology*; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors*; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013997:Time Factors
D004791:Enzyme Inhibitors; D007211:Indoles; D010648:Phenylacetates; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; C501562:prostanoid D receptor 1, human; C030374:indole; D051544:Cytochrome P-450 CYP3A; C025136:phenylacetic acid; C036293:prostaglandin D2 receptor
CRTH2; CYP3A4; DP; Indole; Phenylacetic acid