In a recent post the difficulties of developing drug-like and CNS penetrant inhibitors of β-secretase (BACE-1 or ASP-2) were hinted at (a detailed account of the state of the art can be found in this book). Many of the reported inhibitors contain a central transition-state isostere flanked by fragments resembling the substrate peptide sequence and, as a result, the physicochemical properties of such molecules (i.e. relatively high MW, logP, PSA, and too many H-bond donor/acceptors) tend to result in inhibitors having poor pharmacokinetic properties and a high degree of P-gp mediated efflux from the CNS. Various groups have sought to address these issues by seeking novel, non-peptidic core templates (see this recent review for examples) either by fragment-based methods or by de novo structure-based design. A recent publication from Novartis describes an interesting example of the latter approach which is summarised graphically below:The key hydroxyethylamine motif (which mimics the transition-state during substrate hydrolysis and binds to both of the active site aspartic acid residues), found in many reported inhibitors, was retained but incorporated into a constrained, cyclic core. This core was then decorated with non-peptidic groups designed to access the S1, S3, and S2′ recognition pockets (the structural preferences of which are well documented and highly conserved). Whilst the S2 pocket was not targeted, a functional group X was incorporated into the core with a view to making additional interactions with the protein flap that usually binds over the substrate in the active site (this design approach is similar to that previously reported by DuPont with their cyclic urea, HIV protease inhibitors e.g. Mozenavir). The Novartis group sought to maximise the probability of obtaining CNS penetrant compounds by targeting an appropriate chemical space (MW<450, ClogP<4, PSA<90, H-bond acceptors<5, pKa<7). All candidate structures meeting these criteria were docked into the active site and ranked prior to synthesis. The two compounds shown below were two early compounds they prepared.Whereas the pyran oxygen was unable to form close interactions with the flap the analogous sulfone, which was 50-fold more active, was co-crystallised with BACE (PDB 3PI5) and observed to form optimal H-bonds to Thr72 and Gln73 as hoped. The aromatic substituents were also observed to make close hydrophobic contacts within the S1 and S2′ pockets and the sulfone had the added and desirable effect of lowering the pKa of the amine by just over 1 order of magnitude relative to the pyran. Initial attempts to optimise the potency of this series further by extending into the S3 pocket as originally intended were largely unsuccessful and the biggest improvements in potency were obtained by optimisation of the P2′ group (with t-butyl substitution being most potent, see 22c below). However, significant brain exposure was achieved when 22c was dosed i.v. in mice thus validating the design approach that was taken. The authors promise future disclosures of steps taken to further improve potency and address the low selectivity (vs Cathepsin D) and metabolic stability issues (22c had a half-life of 6 minutes in rat microsomes) associated with these early exemplars from this series.
- Abbott adverse events allosteric allosteric inhibitor amine basicity Analgesic animal PK anti-viral AstraZeneca Aurora beta-secretase bioactivation BIRB-796 Boehringer Ingelheim cancer cardiotoxicity cellular potency CGRP chloro CNS penetration computational method crystal packing CYP450 Deuterium Doramapimod FAAH Fatty acid amide hydrolase fluorine free drug functional antagonist Gly-T1 gpcr hepatotoxicity hERG immunosuppressant isostere kinase kinetic isotope effect Lexicon Pharmaceuticals LipE Merck metabolism mTOR nitrile Novartis osteoarthritis P-gp p38 Pain PF-04457845 PF-3845 Pfizer Phase I Phase II Phase III POC PPB protein binding PSA reactive metabolite review RG1678 rheumatoid arthritis Roche S1P1 S1PL Schizophrenia solubility Structural alert Structure Based Design switch pocket synthesis toxicity Transporters X-ray data