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A series of prolyl-N-isonicotinoyl-(L)-4-aminophenylalanine derivatives substituted at the proline 4-position with cyclic amines was evaluated as VLA-4 antagonists. The ring size and presence or absence of fluorine affected potency and receptor occupancy. The analog with 3,3-difluoropiperidine at the proline 4-position (13) was the most potent compound and had very good duration of receptor occupancy in vitro. The ethyl ester prodrug of 13 demonstrated excellent receptor occupancy after oral dosing in rats.

A series of VLA-4 antagonist were synthesized wherein carboxylic acid was replaced by various acid surrogates. The effect of these acid surrogates toward potency was evaluated in a binding assay. A number of acid surrogates were potent antagonist of VLA-4, albeit significantly less potent than the corresponding carboxylic acid. Heterocyclic acid surrogate, oxadiazolidinone 3, demonstrated an improved pharmacokinetic property when dosed intravenously.

We have identified and synthesized a brain penetrant propanoic acid as an allosteric potentiator of the metabotropic glutamate receptor 2. Structure-activity relationship studies directed toward improving the potency, level of potentiation and brain penetration led to the discovery of 8 (EC50=1200 nM, 77% potentiation, 119% brain/plasma in rat, 20 mpk i.p., brain level of 5700 nM).

We have identified and synthesized a series of phenyl-tetrazolyl and 4-thiopyridyl indanones as allosteric potentiators of the metabotropic glutamate receptor 2. Structure activity relationship studies directed toward improving the potency and level of potentiation, as well as PK properties, led to the discovery of 28 (EC50 = 186 nM), which displayed activity in a rodent model for schizophrenia.

A series of potent, selective platelet-derived growth factor receptor-family kinase inhibitors was optimized starting from a globally selective lead molecule 4 through structural modifications aimed at improving the physiochemical and pharmacokinetic properties, as exemplified by 18b. Further clearance reduction via per-methylation of the α-carbons of a solubilizing piperidine nitrogen resulted in advanced leads 22a and 22b. Results from a mouse tumor xenograft, a collagen-induced arthritis model, and a 7 day rat in vivo tolerability study culminated in the selection of compound 22b (AC710) as a preclinical development candidate.

We have identified and synthesized a series of biphenyl-carboxylic acid indanones as allosteric potentiators of the metabotropic glutamate receptor 2. Structure-activity relationship studies directed toward improving the potency and the brain to plasma ratio of the initial lead led to the discovery of 5 and 23 (EC50=111 and 5 nM, respectively).

We have identified and synthesized a series of 4-thiopyridyl acetophenones as positive allosteric potentiators of the metabotropic glutamate receptor 2. Structure-activity relationship studies directed toward replacement of the tetrazole in the initial lead led to the discovery of 16 (EC(50)=340 nM), which showed improved brain penetration over the initial lead.