Alexander S. Kiselyov

Arylphthalazines as potent, and orally bioavailable inhibitors of VEGFR-2

A series of arylphthalazine derivatives were synthesized and evaluated as antagonists of VEGF receptor II (VEGFR-2). IM-094482 57, which was prepared in two steps from commercially available starting materials, was found to be a potent inhibitor of VEGFR-2 in enzymatic, cellular and mitogenic assays (comparable activity to ZD-6474). Additionally, 57 inhibited the related receptor, VEGF receptor I (VEGFR-1), and showed excellent exposure when dosed orally to female CD-1 mice.

A facile one-pot synthesis of polysubstituted naphthalenes

Abstract Synthesis of the title compounds from (2-trifluoromethyl)phenylacetonitrile is described. The mechanism of the reaction is believed to involve the formation of the quinone methide intermediate.

Synthesis and evaluation of heteroaryl-ketone derivatives as a novel class of VEGFR-2 inhibitors

We have discovered novel inhibitors of VEGFR-2 kinase with low nanomolar potency in both enzymatic and cell-based assays. Active series are heteroaryl-ketone compounds containing a central aromatic ring with either an indazolyl or indolyl keto group in the ortho orientation to the benzylic amine group (Fig. 1). The best compounds were demonstrated to be inactive against a small select panel of tyrosine and serine/threonine kinases with the exception of VEGFR-1 kinase, a close family member. In addition, the lead candidate 8 displayed acceptable exposure levels when administered orally to mice.

A novel synthesis of polysubstituted naphthalenes

Abstract The reaction of (2-trifluoromethyl)phenyl acetic acid derivatives with anions derived from aromatic acetonitriles furnishes polysubstituted naphthalenes in good yields (30–68%). A solid-phase version of this reaction is reported as well. The transformation is proposed to proceed via the intermediate formation of the quinone methide intermediate.