DEVELOPMENT OF AN IMPROVED IN VIVO TOOL COMPOUND, VU6001221, FOR NON-COMPETITIVE INHIBITION OF CHT, DISCOVERY AND DEVELOPMENT OF M1 PAMS: BENZOMORPHOLINE AND TETRAHYDROQUINOLINE SERIES, AND DEVELOPMENT OF NOVEL, BRAIN-PENETRANT PAR4 ANTAGONISTS
Here in, we describe the optimization of high-affinity, choline up-take transporter (CHT) antagonist, ML352, to improved in vivo tool compound, VU6001221. VU6001221, a potent and selective CHT inhibitor with significantly improved pharmacokinetics and CNS penetration, was developed by attenuating the electronics of ML352 using traditional medicinal chemistry approaches. Contrary to our expectations, CHT antagonist VU6001221 displayed a procognitive effect in the novel object recognition paradigm. Further mechanistic studies are necessary to determine the elusive mode of cognitive enhancement within this system. Also described here is the development of muscarinic acetylcholine receptor 1 (M1) positive allosteric modulator (PAM), VU0486846, devoid of adverse cholinergic effects and displaying procognitive efficacy in rodent models of cognition. Scaffold hopping from the quinolone core of BQCA to the benzomorpholine core, followed by medicinal chemistry optimization, eliminated agonist activity and thus, cholinergic toxicity. In addition, through these efforts we discovered that the closely related tetrahydroquinoline analog was equipotent to VU0486846; challenging the generalized notion that an intramolecular hydrogen bond is imperative for M1 PAM activity. Finally, we summarize our efforts towards the development of highly CNS-penetrant protease activated receptor (PAR)4 antagonists with cross-over activity in human and mouse PAR4. Competitive PAR4 antagonist in this novel, chiral series display a divergence in activities between GG and AA single nucleotide polymorphism (SNPs). In addition, we identified a mode switch from PAR4 to PAR1 antagonists by altering the amide moiety to a fused, heterocyclic ring system, which can be utilized for further development of selective PAR1 inhibitors. Efforts are ongoing to improve upon poor drug metabolism and pharmacokinetic properties for the development of an acceptable in vivo PAR4 antagonist.