Rho-associated kinase (ROCK) is an enzyme involved in control of the actin-myosin cytoskeleton, and thus affects smooth muscle contraction, cell migration, and proliferation.  We have found a series of novel benzoxaborole ROCK 1/2 inhibitors including AN3484 that showed IC50 values of 7.5 mM and 2.6 mM against ROCK 1 and ROCK 2, respectively.  X-ray co-crystal structure of AN3484-ROCK 2 complex revealed that the hydroxy group of the oxaborole ring acting as a hydrogen bond donor and the ring oxygen acting as an acceptor in the hinge region of the enzyme, representing a novel chemical motif of a hydrogen bond donor/acceptor pair.  AN3485, a close analog of AN3484, showed better oral bioavailability than AN3484 in mice and oral blood pressure lowering efficacy in spontaneously hypertensive rats.  AN3485 also showed potent anti-inflammatory activity both in vitro and in vivo, suggesting possible applications in lung inflammatory diseases.   The SAR will be discussed.

Boron-based Rho-associated kinase (ROCK) inhibitor: A novel approach to interact with the hinge region and the structure-activity relationships

243rd National Meeting (2012)

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