TABLE 3

Nonprostanoid IP receptor agonists

Binding IC₅₀ refers to competitive binding with radiolabeled iloprost in human platelets. Functional IC₅₀ refers to inhibition of ADP-induced platelet aggregation in human platelet-rich plasma.

Groups and Subgroups	Representative Compound	Pharmacokinetics and Pharmacodynamics			Reference
		K_i	IC₅₀
		K_i	Binding	Functional
			μM	μM
IP agonists
Tetrahydro-naphthalene oxyacetic acid derivatives
4-Benzhydryl-oxyimines	ONO-AP-227		0.15	0.15	Kondo and Hamanaka, 1995; Tsubaki et al., 2000
Oximes/amides/ethers	Compound 12		0.01	0.057
4-Benzhydryl pyrazoles	ONO-AP-437		0.008	0.026
Pyridazinones	FR181877	0.094		0.081
Diphenyloxazole derivatives					Meanwell et al., 1992a;
Cyclohexenes	FR181157	∼0.054		≈0.060	Hattori et al., 2005a,b
Tetrahydro-naphthalenes and pyrrolidines	FR193262	∼0.012		0.019 ± 0.0038
Diphenylcarbamate derivatives with a tetrahydro-naphthalene skeleton	FK788	0.02		0.01	Hattori et al., 2005c
2 Amino-5,6 diphenylpyrazine derivatives	NS-304	0.02		0.2	Asaki et al., 2007
IP partial agonists
Phenylated pyrazol alkanoic acid derivatives (Octimibate-like)
Triphenylated pyrazol alkanoic acids	BMY 42239		0.16	0.4	Meanwell et al., 1992a,b; Seiler et al., 1997
Diphenyloxazole derivatives demonstrating partial agonist activity	BMY42393		0.245	1.2
	BMY45778		∼0.0068	0.035 ± 0.012
IP agonist/TXAS inhibitor
Tetrahydro-naphthalene 5-oxyacetic acid derivatives with a 3-pyridyl instead of phenyl group	ONO-AP-500-02 (ONO-1301)			0.24^{^a} 0.04^{^b}	Kondo et al., 1995
IP agonist/TXA2 antagonist
Benzofuran sulfides	DHMB-acetic acid (Compound 9b)			2.2 ± 0.4^{^c}	Ohno et al., 2005
Benzofuran sulfides	DHMB-acetic acid (Compound 9b)			0.17 ± 0.01^{^d}	Ohno et al., 2005
3,4-Dihydro-2H benzo oxazine derivatives	TRA-418			1.8^{^c}	Ohno et al., 2006
3,4-Dihydro-2H benzo oxazine derivatives	TRA-418			0.55^{^d}	Ohno et al., 2006
PG endoperoxide analogs with diphenylmethyl oxime or azine residues in the ω-chain	EP157			0.5^{^c}	Armstrong et al., 1986
	EP157			0.3^{^d}	Armstrong et al., 1986

BMY 42239, Meanwell et al. (1992b); BMY 42393, 2-[3-[2-(4,5-diphenyl-2-oxazolyl)ethyl]phenoxy]acetic acid; BMY 45778, [3-[4-(4,5-diphenyl-2-oxazolyl)-5-oxazolyl]phenoxy]acetic acid; Compound 12, Kondo and Hamanaka (1995); DHMB-acetic acid, (3-(2-(1,1-diphenylethylsulfanyl)ethyl)-2-hydroxymethylbenzofuran-7-yloxy)acetic acid; EP157, rac-5-endo-(6′-carboxyhex-2′-Z-enyl)-6-exo-diphenylmethoxyiminomethyl-bicyclo[2.2.2]oct-2-ene; FK788, 2-[[(6R)-6-(diphenylcarbamoyloxymethyl)-6-hydroxy-7,8-dihydro-5H-naphthalen-1-yl]oxy]acetic acid; FR181157, sodium (3-{[(1S)-2-(4,5-diphenyl-1,3-oxazol-2-yl)-2-cyclohexen-1-yl]methyl}phenoxy)acetate; FR181877, [[(2S)-2β-(3-oxo-6-benzhydryl-2,3-dihydropyridazine-2-ylmethyl)-5-tetralinyl]oxy]acetic acid; FR193262, sodium ({(5R)-5-[(2R)-2-(4,5-diphenyl-1,3-oxazol-2-yl)pyrrolidin-1-yl]-5,6,7,8-tetrahydronaphthalen-1-yl}oxy)acetate; NS-304, 2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)-N-(methylsulfonyl)acetamide; ONO-AP-227, Kondo and Hamanaka (1995); ONO-AP-437, Kondo and Hamanaka (1995); ONO-AP-500-02, 7,8-dihydro-5-(2-((α-(3-pyridyl)benzylideneaminooxy)ethyl)-1-naphthyloxy)acetic acid; TRA-418, (4-(2-(1,1-diphenylethylsulfanyl)ethyl)-3,4-dihydro-2H-benzo(1,4)oxazin-8-yloxy)acetic acid N methyl-d-glucamine salt.
↵a IP agonist.
↵b TXAS inhibition.
↵c ADP-induced.
↵d U46619-induced.