Immunogenicity of MultiTEP platform technology-based Tau vaccine in non-human primates.

Pathological forms of Tau protein are directly associated with neurodegeneration and correlate with Alzheimer's Disease (AD) symptoms, progression, and severity. Previously, using various mouse models of Tauopathies and AD, we have demonstrated the immunogenicity and efficacy of the MultiTEP-based adjuvanted vaccine targeting the phosphatase activating domain (PAD) of Tau, AV-1980R/A. Here, we analyzed its immunogenicity in non-human primates (NHP), the closest phylogenic relatives to humans with a similar immune system, to initiate the transition of this vaccine into clinical trials.

Sheep recombinant IGF-1 promotes organ-specific growth in fetal sheep.

IGF-1 is a critical fetal growth-promoting hormone. Experimental infusion of an IGF-1 analog, human recombinant LR3 IGF-1, into late gestation fetal sheep increased fetal organ growth and skeletal muscle myoblast proliferation. However, LR3 IGF-1 has a low affinity for IGF binding proteins (IGFBP), thus reducing physiologic regulation of IGF-1 bioavailability.

BMS-813160: A Potent CCR2 and CCR5 Dual Antagonist Selected as a Clinical Candidate.

BMS-813160 (compound ) was identified as a potent and selective CCR2/5 dual antagonist. Compound displayed good permeability at pH = 7.4 in PAMPA experiments and demonstrated excellent human liver microsome stability.

Discovery of BMS-753426: A Potent Orally Bioavailable Antagonist of CC Chemokine Receptor 2.

To improve the metabolic stability profile of BMS-741672 (), we undertook a structure-activity relationship study in our trisubstituted cyclohexylamine series. This ultimately led to the identification of (BMS-753426) as a potent and orally bioavailable antagonist of CCR2. Compared to previous clinical candidate , the -butyl amine showed significant improvements in pharmacokinetic properties, with lower clearance and higher oral bioavailability.

Azatricyclic Inverse Agonists of RORγt That Demonstrate Efficacy in Models of Rheumatoid Arthritis and Psoriasis.

Structure-activity relationship studies directed toward the replacement of the fused phenyl ring of the lead hexahydrobenzoindole RORγt inverse agonist series represented by with heterocyclic moieties led to the identification of three novel aza analogs -. The hexahydropyrrolo[3,2-]quinoline series (X = N, Y = Z=CH) showed potency and metabolic stability comparable to series but with improved membrane permeability and serum free fraction. This structural modification was applied to the hexahydrocyclopentanaphthalene series , culminating in the discovery of as a potent and selective RORγt inverse agonist with an excellent profile, good pharmacokinetic properties, and biologic-like efficacy in preclinical models of rheumatoid arthritis and psoriasis.