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In the inhibition of specific binding of [~:Sl]endothelins (ETs) to membranes from various tissues of rats, guinea pigs, pigs and humans, [Cys ~'-Cyst~]-ET-l( I 1-21 ), IRL 1038, has a much higher affinity for ETa receptors (Ki -6-11 nM) than for ET,., receptors (Ka = 0.4-0.7,a M). In contraction a.~ays, with ET-3 as a stimulant, 3 ,aM IRL 1038 antagonized the ET~ receptor-mediated contraction of guinea pig ileal and tracheal smooth muscle without any significant agonistie activity, but did not effect the ETA receptor-mediated contraction of rat aortic smooth muscle. IRL 1038 is, therefore, considered to be the first antagonist selective to the ETn receptor.

A series of 2-amino-9-aryl-7H-pyrrolo[2,3-d]pyrimidines were designed and synthesized as focal adhesion kinase (FAK) inhibitors using molecular modeling in conjunction with a co-crystal structure. Chemistry was developed to introduce functionality onto the 9-aryl ring, which resulted in the identification of potent FAK inhibitors. In particular, compound 32 possessed single-digit nanomolar IC(50) and represents one of the most potent FAK inhibitors discovered to date.

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