Larry Davis

Synthesis and preliminary structure-activity relationships of 1-[(3-fluoro-4-pyridinyl)amino]-3-methyl-1H-indol-5-yl methyl carbamate (P10358), a novel acetylcholinesterase inhibitor

Abstract A series of carbamate analogs of besipirdine (HP 749) was synthesized as potential agents with enhanced cholinomimetic properties for the treatment of Alzheimers disease. Compound 5a (P10358, 1-[3-fluoro-4-pyridinyl)amino]-3-methyl-1H-indol-5-yl methyl carbamate) emerged as a potent, reversible acetylcholinesterase inhibitor that significantly enhanced performance on oral or parenteral administration in learning and memory paradigms.

4-aminopyridine derivatives: A family of novel modulators of voltage-dependent sodium channels

The interactions of a family of aminopyridine derivatives with Site II of the voltage‐dependent sodium channel were examined by measuring the ability of these compounds to inhibit [3H]batrachotoxin binding and veratridine‐induced increases in [Ca2+]i. Aminopyridines substituted with indole, carbazole, and pyrrole rings were evaluated. All compounds that had an aromatic ring linked to the amine group of 4‐aminopyridine showed positive results in both assays. For example, the most potent compound, besipirdine (N‐(n‐propyl)‐N‐(4‐pyridinyl)‐1H‐indol‐1‐amine), had IC50 values of 5 μM and 23.8 μM in the two assays, respectively. Small substitutions on either the aromatic ring or on 4‐aminopyridine did not substantially change their potencies. Indoles linked to the amino group of 2‐ and 3‐aminopyridine also showed positive results. These results indicate that aminopyridine derivatives substituted with an aromatic ring on the amino nitrogen are inhibitors of voltage‐dependent sodium channels. Drug Dev. Res. 44:8–13, 1998.

Design and synthesis of D1 agonist/D2 antagonist for treatment of schizophrenia

A series of tetrahydroisoquinolines were designed, synthesized and evaluated as the first non-natural product type of compounds with dual D(1) receptor (D(1)R) agonism and D(2) receptor (D(2)R) antagonism properties for treatment of schizophrenia. The initial SAR of the series was explored. The lead in the series, 3g, exhibited high affinity and good potency. Compound 3g displayed 95% of D(1)R occupancy (10 mg/kg, sc) and 75% of D(2)R occupancy (10 mg/kg, sc) in the striatum of male CD-1 mice. The series exhibited unique pharmacology and merit as tool compounds for target validation and future optimizations.

P11467: An Orally-Active Acetylcholinesterase Inhibitor and α 2 -Adrenoceptor Antagonist for Alzheimer’s Disease

Alzheimer’s disease (AD) is a complex and multifaceted neurodegenerative disease characterized by cognitive and behavioral abnormalities. The primary cognitive deficit has been correlated with extensive cholinergic dysfunction and the efficacy of cholinergic therapies in this disease validates and supports the cholinergic hypothesis of AD (Weinstock, 1995). To date, tacrine has shown clinical efficacy in 20 to 30% of AD patients and remains the only acetylcholinesterase inhibitor (AChEI) to receive FDA approval for symptomatic treatment (Knapp et al., 1994). However, the limited efficacy of pure cholinergic therapies suggests that other neurochemical deficiencies are involved.