Discovery of Clinical Candidate PF-06648671: A Potent γ-Secretase Modulator for the Treatment of Alzheimer's Disease.

Herein, we describe the design and synthesis of γ-secretase modulator (GSM) clinical candidate PF-06648671 () for the treatment of Alzheimer's disease. A key component of the design involved a 2,5--tetrahydrofuran (THF) linker to impart conformational rigidity and lock the compound into a putative bioactive conformation. This effort was guided using a pharmacophore model since crystallographic information was not available for the membrane-bound γ-secretase protein complex at the time of this work.

Discovery and Preclinical Characterization of BIIB129, a Covalent, Selective, and Brain-Penetrant BTK Inhibitor for the Treatment of Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic disease with an underlying pathology characterized by inflammation-driven neuronal loss, axonal injury, and demyelination. Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase and member of the TEC family of kinases, is involved in the regulation, migration, and functional activation of B cells and myeloid cells in the periphery and the central nervous system (CNS), cell types which are deemed central to the pathology contributing to disease progression in MS patients. Herein, we describe the discovery of BIIB129 (), a structurally distinct and brain-penetrant targeted covalent inhibitor (TCI) of BTK with an unprecedented binding mode responsible for its high kinome selectivity.

Photoaffinity Labeling and Quantitative Chemical Proteomics Identify LXRβ as the Functional Target of Enhancers of Astrocytic apoE.

Utilizing a phenotypic screen, we identified chemical matter that increased astrocytic apoE secretion in vitro. We designed a clickable photoaffinity probe based on a pyrrolidine lead compound and carried out probe-based quantitative chemical proteomics in human astrocytoma CCF-STTG1 cells to identify liver x receptor β (LXRβ) as the target. Binding of the small molecule ligand stabilized LXRβ, as shown by cellular thermal shift assay (CETSA).

Synthetic Approaches to New Drugs Approved during 2018.

New drugs introduced to the market every year represent privileged structures for particular biological targets. These new chemical entities (NCEs) provide insight into molecular recognition while serving as leads for designing future new drugs. This annual review describes the most likely process-scale synthetic approaches to 39 new chemical entities approved for the first time globally in 2018.

5-Aryltetrazoles from Direct C-H Arylation with Aryl Bromides.

A mild, direct C-H arylation of 1-substituted tetrazoles to 5-aryltetrazoles is developed using a Pd/Cu cocatalytic system with readily available aryl bromides. The methodology avoids late-stage usage of azides and tolerates a wide range of functionalities.

High-Throughput Ligand Screening Enables the Enantioselective Conjugate Borylation of Cyclobutenones to Access Synthetically Versatile Tertiary Cyclobutylboronates.

Cyclobutane rings are important in medicinal chemistry, yet few enantioselective methods exist to access this scaffold. In particular, cyclobutylboronates are receiving increasing attention in the literature due to the synthetic versatility of alkylboronic esters and the increasing role of boronic acids in drug discovery. Herein, a conjugate borylation of α-alkyl,β-aryl/alkyl cyclobutenones is reported leading to the first synthesis of enantioenriched tertiary cyclobutylboronates.

Quick Building Blocks (QBB): An Innovative and Efficient Business Model To Speed Medicinal Chemistry Analog Synthesis.

Many pharmaceutical companies have invested millions of dollars in establishing internal chemical stores to provide reliable access to large numbers of building blocks (BB) for the synthesis of new molecules, especially for the timely design and execution of parallel (library) synthesis. Recognizing budget and logistical limitations, we required a more economically scalable process to provide diverse BB. We disclose a novel business partnership that achieves the goals of just-in-time, economical access to commercial BB that increases chemical space coverage and accelerates the synthesis of new drug candidates.

Synthetic Approaches to the New Drugs Approved During 2017.

New drugs introduced to the market every year represent privileged structures for particular biological targets. These new chemical entities (NCEs) provide insight into molecular recognition while serving as leads for designing future new drugs. This annual review describes the most likely process-scale synthetic approaches to 31 new chemical entities approved for the first time globally in 2017.

Discovery and Lead Optimization of Atropisomer D1 Agonists with Reduced Desensitization.

The discovery of D1 subtype-selective agonists with drug-like properties has been an enduring challenge for the greater part of 40 years. All known D1-selective agonists are catecholamines that bring about receptor desensitization and undergo rapid metabolism, thus limiting their utility as a therapeutic for chronic illness such as schizophrenia and Parkinson's disease. Our high-throughput screening efforts on D1 yielded a single non-catecholamine hit PF-4211 (6) that was developed into a series of potent D1 receptor agonist leads with high oral bioavailability and CNS penetration.

Discovery of Trifluoromethyl Glycol Carbamates as Potent and Selective Covalent Monoacylglycerol Lipase (MAGL) Inhibitors for Treatment of Neuroinflammation.

Monoacylglycerol lipase (MAGL) inhibition provides a potential treatment approach to neuroinflammation through modulation of both the endocannabinoid pathway and arachidonoyl signaling in the central nervous system (CNS). Herein we report the discovery of compound 15 (PF-06795071), a potent and selective covalent MAGL inhibitor, featuring a novel trifluoromethyl glycol leaving group that confers significant physicochemical property improvements as compared with earlier inhibitor series with more lipophilic leaving groups. The design strategy focused on identifying an optimized leaving group that delivers MAGL potency, serine hydrolase selectivity, and CNS exposure while simultaneously reducing log  D, improving solubility, and minimizing chemical lability.

Late-Stage Microsomal Oxidation Reduces Drug-Drug Interaction and Identifies Phosphodiesterase 2A Inhibitor PF-06815189.

Late-stage oxidation using liver microsomes was applied to phosphodiesterase 2 inhibitor to reduce its clearance by cytochrome P450 enzymes, introduce renal clearance, and minimize the risk for victim drug-drug interactions. This approach yielded PF-06815189 () with improved physicochemical properties and a mixed metabolic profile. This example highlights the importance of C-H diversification methods to drug discovery.

A platform for automated nanomole-scale reaction screening and micromole-scale synthesis in flow.

The scarcity of complex intermediates in pharmaceutical research motivates the pursuit of reaction optimization protocols on submilligram scales. We report here the development of an automated flow-based synthesis platform, designed from commercially available components, that integrates both rapid nanomole-scale reaction screening and micromole-scale synthesis into a single modular unit. This system was validated by exploring a diverse range of reaction variables in a Suzuki-Miyaura coupling on nanomole scale at elevated temperatures, generating liquid chromatography-mass spectrometry data points for 5760 reactions at a rate of >1500 reactions per 24 hours.

Introduction of a Crystalline, Shelf-Stable Reagent for the Synthesis of Sulfur(VI) Fluorides.

The design, synthesis, and application of [4-(acetylamino)phenyl]imidodisulfuryl difluoride (AISF), a shelf-stable, crystalline reagent for the synthesis of sulfur(VI) fluorides, is described. The utility of AISF is demonstrated in the synthesis of a diverse array of aryl fluorosulfates and sulfamoyl fluorides under mild conditions. Additionally, a single-step preparation of AISF was developed that installed the bis(fluorosulfonyl)imide group on acetanilide utilizing an oxidative C-H functionalization protocol.

Identification of a Potent, Highly Selective, and Brain Penetrant Phosphodiesterase 2A Inhibitor Clinical Candidate.

Computational modeling was used to direct the synthesis of analogs of previously reported phosphodiesterase 2A (PDE2A) inhibitor 1 with an imidazotriazine core to yield compounds of significantly enhanced potency. The analog PF-05180999 (30) was subsequently identified as a preclinical candidate targeting cognitive impairment associated with schizophrenia. Compound 30 demonstrated potent binding to PDE2A in brain tissue, dose responsive mouse brain cGMP increases, and reversal of N-methyl-d-aspartate (NMDA) antagonist-induced (MK-801, ketamine) effects in electrophysiology and working memory models in rats.

Ru/Ni Dual Catalytic Desulfinative Photoredox C-C Cross-Coupling of Alkyl Sulfinate Salts and Aryl Halides.

A mild Ru/Ni dual catalytic desulfinative photoredox C-C cross-coupling reaction of alkyl sulfinate salts with aryl halides has been developed. The optimized catalyst system, consisting of Ru(bpy)Cl, Ni(COD), and DBU, smoothly mediates the coupling of a diverse set of secondary and primary nonactivated alkyl sulfinate salts with a broad range of electron-deficient aryl bromides, electron-rich aryl iodides, and heteroaryl bromides under irradiation with blue light. The procedure is ideal for late-stage introduction of alkyl groups on pharmaceutical intermediates, and the C-C cross-coupling reaction allowed the rapid synthesis of caseine kinase 1δ inhibitor analogues via a parallel medicinal chemistry effort.

Parallel Synthesis of 1H-Pyrazolo[3,4-d]pyrimidines via Condensation of N-Pyrazolylamides and Nitriles.

A novel parallel medicinal chemistry (PMC)-enabled synthesis of 1H-pyrazolo[3,4-d]pyrimidines employing condensation of easily accessible N-pyrazolylamides and nitriles has been developed. The presented studies describe singleton and library enablements that allowed rapid generation of molecular diversity to examine C4 and C6 vectors. This chemistry enabled access to challenging alkyl substituents, expanding the overall chemical space beyond that available via typical C(sp)-C(sp) coupling and SAr transformations.

The Discovery of a Novel Phosphodiesterase (PDE) 4B-Preferring Radioligand for Positron Emission Tomography (PET) Imaging.

As part of our effort in identifying phosphodiesterase (PDE) 4B-preferring inhibitors for the treatment of central nervous system (CNS) disorders, we sought to identify a positron emission tomography (PET) ligand to enable target occupancy measurement in vivo. Through a systematic and cost-effective PET discovery process, involving expression level (B) and biodistribution determination, a PET-specific structure-activity relationship (SAR) effort, and specific binding assessment using a LC-MS/MS "cold tracer" method, we have identified 8 (PF-06445974) as a promising PET lead. Compound 8 has exquisite potency at PDE4B, good selectivity over PDE4D, excellent brain permeability, and a high level of specific binding in the "cold tracer" study.

Aminomethyl-Derived Beta Secretase (BACE1) Inhibitors: Engaging Gly230 without an Anilide Functionality.

A growing subset of β-secretase (BACE1) inhibitors for the treatment of Alzheimer's disease (AD) utilizes an anilide chemotype that engages a key residue (Gly230) in the BACE1 binding site. Although the anilide moiety affords excellent potency, it simultaneously introduces a third hydrogen bond donor that limits brain availability and provides a potential metabolic site leading to the formation of an aniline, a structural motif of prospective safety concern. We report herein an alternative aminomethyl linker that delivers similar potency and improved brain penetration relative to the amide moiety.

Discovery of cyclopropyl chromane-derived pyridopyrazine-1,6-dione γ-secretase modulators with robust central efficacy.

Herein we describe the discovery of a novel series of cyclopropyl chromane-derived pyridopyrazine-1,6-dione γ-secretase modulators for the treatment of Alzheimer's disease (AD). Using ligand-based design tactics such as conformational analysis and molecular modeling, a cyclopropyl chromane unit was identified as a suitable heterocyclic replacement for a naphthyl moiety that was present in the preliminary lead . The optimized lead molecule achieved good central exposure resulting in robust and sustained reduction of brain amyloid-β42 (Aβ42) when dosed orally at 10 mg kg in a rat time-course study.

Discovery of the Potent and Selective M1 PAM-Agonist N-[(3R,4S)-3-Hydroxytetrahydro-2H-pyran-4-yl]-5-methyl-4-[4-(1,3-thiazol-4-yl)benzyl]pyridine-2-carboxamide (PF-06767832): Evaluation of Efficacy and Cholinergic Side Effects.

It is hypothesized that selective muscarinic M1 subtype activation could be a strategy to provide cognitive benefits to schizophrenia and Alzheimer's disease patients while minimizing the cholinergic side effects observed with nonselective muscarinic orthosteric agonists. Selective activation of M1 with a positive allosteric modulator (PAM) has emerged as a new approach to achieve selective M1 activation. This manuscript describes the development of a series of M1-selective pyridone and pyridine amides and their key pharmacophores.

Preclinical Evaluation of 18F-PF-05270430, a Novel PET Radioligand for the Phosphodiesterase 2A Enzyme.

Unlabelled: The enzyme phosphodiesterase 2A (PF-05270430) is a potential target for development of novel therapeutic agents for the treatment of cognitive impairments. The goal of the present study was to evaluate the PDE2A ligand (18)F-PF-05270430, 4-(3-fluoroazetidin-1-yl)-7-methyl-5-(1-methyl-5-(4-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)imidazo[1,5-f][1,2,4]triazine, in nonhuman primates.

Methods: (18)F-PF-05270430 was radiolabeled by 2 methods via nucleophilic substitution of its tosylate precursor.

Discovery of a series of efficient, centrally efficacious BACE1 inhibitors through structure-based drug design.

The identification of centrally efficacious β-secretase (BACE1) inhibitors for the treatment of Alzheimer's disease (AD) has historically been thwarted by an inability to maintain alignment of potency, brain availability, and desired absorption, distribution, metabolism, and excretion (ADME) properties. In this paper, we describe a series of truncated, fused thioamidines that are efficiently selective in garnering BACE1 activity without simultaneously inhibiting the closely related cathepsin D or negatively impacting brain penetration and ADME alignment, as exemplified by 36. Upon oral administration, these inhibitors exhibit robust brain availability and are efficacious in lowering central Amyloid β (Aβ) levels in mouse and dog.