Updated on 9 July 2012
In the area of inflammation, AMRI identified a selective glucocorticoid receptor modulator (SGRM). This program progressed to the lead optimization phase. AMRI identified compounds to selectively displace the natural ligand from the glucocorticoid receptor. The company developed cell-based assays to identify compounds that could selectively inhibit the expression of inflammatory cytokines, leaving the activities of glucocorticoid response element-mediated pathways unaltered. Portions of AMRI's small molecule and natural product sample libraries were screened for SGRMs and natural product actives were purified and their structures elucidated. Following the use of technologies, which were implemented to determine if mechanisms of action were dependent on the glucocorticoid receptor, several SGRMs were identified. This included a 450 pM natural product, non-steroidal SGRM, which had greater than 50-fold selectivity for transrepression of inflammatory cytokine expression over transactivation of glucocorticoid response element-mediated pathways. Before moving to lead optimization, the compound was purified and the structure elucidated. This compound is no longer available for licensing.
In the area of metabolic diseases, AMRI carried out a fully integrated MCH-1 antagonist drug-discovery program. The MCH-1 antagonist approach was chosen as a target for AMRI's internally funded R&D. The screening strategy, target product profile and differentiation strategy was designed and implemented by the fully integrated AMRI project team. Hits were generated through a dual approach using a screen of library compounds and through rational compound design and selection using a pharmacophore model. Lead optimization drove parameters, such as affinity, selectivity, metabolic stability and in vivo activity. An in vitro target assay was developed around AMRI proprietary radioligand, with in vitro DMPK using AMRI platforms. AMRI directed the design and the validation of in vivo efficacy/novel ex vivo receptor occupancy assays. Of the 1,000 compounds prepared during lead optimization, multiple compounds progressed into advanced in vivo candidate selection studies and ALB-127158(a) was chosen as a pre-clinical candidate. AMRI guided the completion of regulatory safety, toxicity studies and a phase I clinical trial. Overall, the study demonstrated safety/tolerability with a second translational phase I study indicating CNS penetration. AMRI then identified follow-on compounds as a back-up strategy.
AMRI is seeking a partner to progress the research and development of its MCH1 ALB-127158(a) program. The phase I study met both its primary and secondary objectives, demonstrating safety and tolerability, and multiple patent applications have been filed to protect AMRI intellectual property.
AMRI also has experience in the complex therapeutic area of oncology. For one project, a multidisciplinary team of AMRI medicinal chemists, in vitro biologists and DMPK scientists worked together to discover preclinical candidates for two protein kinase targets. AMRI's in vitro biology group developed and validated a client's two kinase assays for HTS. Follow-on activities were performed, which included the screening of AMRI's Diverse Synthetic Library Collection to generate hits; and medicinal chemistry, CADD and in vitro DMPK activities. More than 2,500 compounds were prepared in this program and more than 10 compounds have demonstrated 30% to 90% tumor growth inhibition in vivo upon intravenous dosing on a 14-day efficacy study in nude mice xenograft studies. Mouse pharmacokinetic studies have shown two compounds exhibiting greater than 50 percent oral bioavailability. Two patent applications filed with additional applications pending filing.