Discovery of Potent and Selective Inhibitors of Phosphodiesterase 1 for the Treatment of Cognitive Impairment Associated with Neurodegenerative and Neuropsychiatric Diseases.

A diverse set of 3-aminopyrazolo[3,4-d]pyrimidinones was designed and synthesized. The structure-activity relationships of these polycyclic compounds as phosphodiesterase 1 (PDE1) inhibitors were studied along with their physicochemical and pharmacokinetic properties. Systematic optimizations of this novel scaffold culminated in the identification of a clinical candidate, (6aR,9aS)-2-(4-(6-fluoropyridin-2-yl)benzyl)-5-methyl-3-(phenylamino)-5,6a,7,8,9,9a-hexahydrocyclopenta[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4-(2H)-one phosphate (ITI-214), which exhibited picomolar inhibitory potency for PDE1, demonstrated excellent selectivity against all other PDE families and showed good efficacy in vivo. Currently, this investigational new drug is in Phase I clinical development and being considered for the treatment of several indications including cognitive deficits associated with schizophrenia and Alzheimer's disease, movement disorders, attention deficit and hyperactivity disorders, and other central nervous system (CNS) and non-CNS disorders.

Discovery of a tetracyclic quinoxaline derivative as a potent and orally active multifunctional drug candidate for the treatment of neuropsychiatric and neurological disorders.

We report the synthesis and structure-activity relationships of a class of tetracyclic butyrophenones that exhibit potent binding affinities to serotonin 5-HT(2A) and dopamine D2 receptors. This work has led to the discovery of 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-1-(4-fluorophenyl)-butan-1-one 4-methylbenzenesulfonate (ITI-007), which is a potent 5-HT(2A) antagonist, postsynaptic D2 antagonist, and inhibitor of serotonin transporter. This multifunctional drug candidate is orally bioavailable and exhibits good antipsychotic efficacy in vivo. Currently, this investigational new drug is under clinical development for the treatment of neuropsychiatric and neurological disorders.

Rare-earth amidate complexes. Easily accessed initiators for epsilon-caprolactone ring-opening polymerization.

The direct synthesis of yttrium amidate complexes using the simple reaction of amide proligands and Y(N(SiMe3)2)3 results in the high-yielding preparation and isolation of crystalline, monomeric materials. The complex, tris(N-2',6'-diisopropylphenyl(naphthyl)amidate)yttrium mono(tetrahydrofuran) (4), was structurally determined to be a 7-coordinate C1 symmetric structure, maintaining one bound tetrahydrofuran molecule. Compound 4 (C12H17[NCO]C10H7)3Y(C4H8O) crystallized in the monoclinic space group P2(1)/c with a = 13.7820(11) A, b = 33.598(3) A, c = 16.0575(12) A, alpha = 90 degrees, beta = 98.762(3) degrees, gamma = 90 degrees, Z = 4. Solution phase NMR spectroscopic characterization of this same complex showed a highly symmetric species, consistent with a fluxional coordination environment for these compounds. Preliminary studies into the initiation of epsilon-caprolactone ring-opening polymerization using these complexes indicate high activity, producing high molecular weight polymer.

Intramolecular hydroamination of unactived olefins with Ti(NMe2)4 as a precatalyst.

Commercially available Ti(NMe(2))(4) has been used effectively as a precatalyst in a facile protocol for the intramolecular hydroamination of aminoalkenes to yield pyrrolidine and piperidine heterocyclic products with isolated yields up to 92%. Geminally substituted substrates display the highest reactivity. This precatalyst is also effective for the hydroamination of activated internal alkenes, providing access to more complex heterocyclic target molecules.