. 2024 May 29;138(11):645–662. doi: 10.1042/CS20240249

Table 1. In vitro binding affinities and in vivo pressor inhibition of orally administered ET_AR and AT₁R antagonists through development and optimization.

Target receptor (s)	Antagonist name	ET_AR K_i (nM)	AT₁R K_i (nM)	ET_BR K_i (nM)	AT₂R K_i (nM)	Oral big ET-1 pressor (30 µM/kg) (AOC units)*	Oral Ang II pressor (30 µM/kg) (AOC units)*
ET_AR	BMS-193884	1.4^†	>10,000^†	-	-	10,100^*	Inactive^*
AT₁R	Irbesartan	>10,000^†	1.1^†	-	-	Inactive^*	11,940^*
ET_AR & AT₁R	Unnamed biphenylsulfonamide	39^†	ND^†	-	-	-	-
ET_AR & AT₁R	BMS-248360	1.9^†	10^†	-	-	7,900^*	6,000^*
ET_AR & AT₁R	BMS-346567 (sparsentan)	9.3^*	0.8^*	>10,000^*	>10,000^*	15,800^*	18,600^*

The chemical structures of the mono-selective antagonists BMS-193884 and irbesartan were merged to produce the first-generation dual ET_AR/AT₁R antagonist, an unnamed biphenylsulfonamide. Optimization regained the original target ET_AR activity (BMS-248360). Further optimization retained dual specificity while improving bioavailability in dog and monkey and oral pressor inhibition in rat (BMS-346567/sparsentan, bioavailability data not shown).

Abbreviations: ‘-’ = not shown; AOC, area over curve, indicating potency and duration of action at equimolar doses; AT₁R, AT₁ receptor; ET_AR, ET receptor type A; K_i, inhibitory constant; ND, not determined.

Murugesan 2005 [107].

^†

Murugesan 2002 [2].

Table 1. In vitro binding affinities and in vivo pressor inhibition of orally administered ETAR and AT1R antagonists through development and optimization.

Table 1. In vitro binding affinities and in vivo pressor inhibition of orally administered ET_AR and AT₁R antagonists through development and optimization.