Discovery of Highly Selective Inhibitors of Microtubule-Associated Serine/Threonine Kinase-like (MASTL).

By virtue of its role in cellular proliferation, microtubule-associated serine/threonine kinase-like (MASTL) represents a novel target and a first-in-class (FIC) opportunity to provide a new impactful therapeutic agent to oncology patients. Herein, we describe a hit-to-lead optimization effort that resulted in the delivery of two highly selective MASTL inhibitors. Key strategies leveraged to enable this work included structure-based drug design (SBDD), analysis of lipophilic efficiency (LipE) and novel synthesis.

Visible-Light-Initiated Manganese Catalysis for C-H Alkylation of Heteroarenes: Applications and Mechanistic Studies.

A visible-light-driven Minisci protocol that employs an inexpensive earth-abundant metal catalyst, decacarbonyldimanganese Mn (CO) , to generate alkyl radicals from alkyl iodides has been developed. This Minisci protocol is compatible with a wide array of sensitive functional groups, including oxetanes, sugar moieties, azetidines, tert-butyl carbamates (Boc-group), cyclobutanes, and spirocycles. The robustness of this protocol is demonstrated on the late-stage functionalization of complex nitrogen-containing drugs.

Modern advances in heterocyclic chemistry in drug discovery.

New advances in synthetic methodologies that allow rapid access to a wide variety of functionalized heterocyclic compounds are of critical importance to the medicinal chemist as it provides the ability to expand the available drug-like chemical space and drive more efficient delivery of drug discovery programs. Furthermore, the development of robust synthetic routes that can readily generate bulk quantities of a desired compound help to accelerate the drug development process. While established synthetic methodologies are commonly utilized during the course of a drug discovery program, the development of innovative heterocyclic syntheses that allow for different bond forming strategies are having a significant impact in the pharmaceutical industry.

Driving external chemistry optimization via operations management principles.

Confronted with the need to significantly raise the productivity of remotely located chemistry CROs Pfizer embraced a commitment to continuous improvement which leveraged the tools from both Lean Six Sigma and queue management theory to deliver positive measurable outcomes. During 2012 cycle times were reduced by 48% by optimization of the work in progress and conducting a detailed workflow analysis to identify and address pinch points. Compound flow was increased by 29% by optimizing the request process and de-risking the chemistry.

Synthesis and biological evaluation of substituted benzoxazoles as inhibitors of mPGES-1: use of a conformation-based hypothesis to facilitate compound design.

Microsomal prostaglandin E(2) synthase-1 (mPGES-1) is a novel therapeutic target for the treatment of inflammation and pain. In the preceding letter, we detailed the discovery of clinical candidate PF-04693627, a potent mPGES-1 inhibitor possessing a novel benzoxazole structure. While PF-04693627 was undergoing further preclinical profiling, we sought to identify a back-up mPGES-1 inhibitor that differentiated itself from PF-04693627.

Discovery and SAR of PF-4693627, a potent, selective and orally bioavailable mPGES-1 inhibitor for the potential treatment of inflammation.

Inhibition of mPGES-1, the terminal enzyme in the arachidonic acid/COX pathway to regulate the production of pro-inflammatory prostaglandin PGE2, is considered an attractive new therapeutic target for safe and effective anti-inflammatory drugs. The discovery of a novel series of orally active, selective benzoxazole piperidinecarboxamides as mPGES-1 inhibitors is described. Structure-activity optimization of lead 5 with cyclohexyl carbinols resulted in compound 12, which showed excellent in vitro potency and selectivity against COX-2, and reasonable pharmacokinetic properties.

Acidic triazoles as soluble guanylate cyclase stimulators.

A series of acidic triazoles with activity as soluble guanylate cyclase stimulators is described. Incorporation of the CF(3) triazole improved the overall physicochemical and drug-like properties of the molecule and is exemplified by compound 25.

MMP-13 selective alpha-sulfone hydroxamates: identification of selective P1' amides.

Continuing our interest in designing compounds preferentially potent and selective for MMP-13, we report on a series of hydroxamic acids with a flexible amide P1' substituents. We identify an amide which spares both MMP-1 and -14, and shows >500 fold selectivity for MMP-13 versus MMP-2 and -8.

Design, synthesis, and biological evaluation of 3-[4-(2-hydroxyethyl)piperazin-1-yl]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one, a potent, orally active, brain penetrant inhibitor of phosphodiesterase 5 (PDE5).

We recently described a novel series of aminopyridopyrazinones as PDE5 inhibitors. Efforts toward optimization of this series culminated in the identification of 3-[4-(2-hydroxyethyl)piperazin-1-yl]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one, which possessed an excellent potency and selectivity profile and demonstrated robust in vivo blood pressure lowering in a spontaneously hypertensive rat (SHR) model. Furthermore, this compound is brain penetrant and will be a useful agent for evaluating the therapeutic potential of central inhibition of PDE5.

Optimization of the aminopyridopyrazinones class of PDE5 inhibitors: discovery of 3-[(trans-4-hydroxycyclohexyl)amino]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one.

We describe efforts to improve the pharmacokinetic profile of the aminopyridopyrazinone class of PDE5 inhibitors. These efforts led to the discovery of 3-[(trans-4-hydroxycyclohexyl)amino]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one, a potent and selective inhibitor of PDE5 with an excellent PK profile.

Identification, synthesis and SAR of amino substituted pyrido[3,2b]pyrazinones as potent and selective PDE5 inhibitors.

A new class of potent and selective PDE5 inhibitors is disclosed. Guided by X-ray crystallographic data, optimization of an HTS lead led to the discovery of a series of 2-aryl, (N8)-alkyl substituted-6-aminosubstituted pyrido[3,2b]pyrazinones which show potent inhibition of the PDE5 enzyme. Synthetic details and some structure-activity relationships are also presented.

Investigation of aminopyridiopyrazinones as PDE5 inhibitors: Evaluation of modifications to the central ring system.

Efforts to improve the potency and physical properties of the aminopyridiopyrazinone class of PDE5 inhibitors through modification of the core ring system are described. Five new ring systems are evaluated and features that impart improved potency and improved solubility are delineated.

Physiochemical drug properties associated with in vivo toxicological outcomes.

Relationships between physicochemical drug properties and toxicity were inferred from a data set consisting of animal in vivo toleration (IVT) studies on 245 preclinical Pfizer compounds; an increased likelihood of toxic events was found for less polar, more lipophilic compounds. This trend held across a wide range of types of toxicity and across a broad swath of chemical space.

Design of potent inhibitors of human beta-secretase. Part 2.

We describe an optimized series of acyclic hydroxyethylamine transition state isosteres of beta-secretase that incorporates a variety of P(2) side chains that yield potent inhibitors with excellent cellular activity. A 2.2A crystal structure of compound 13 is shown.

Design of potent inhibitors of human beta-secretase. Part 1.

We describe a novel series of potent inhibitors of human beta-secretase. These compounds possess the hydroxyethyl amine transition state isostere. A 2.

Discovery of a simple picomolar inhibitor of cholesteryl ester transfer protein.

A novel series of substituted N-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-N-(3-phenoxyphenyl)-trifluoro-3-amino-2-propanols is described which potently and reversibly inhibit cholesteryl ester transfer protein (CETP). Starting from the initial lead 1, various substituents were introduced into the 3-phenoxyaniline group to optimize the relative activity for inhibition of the CETP-mediated transfer of [3H]-cholesteryl ester from HDL donor particles to LDL acceptor particles either in buffer or in human serum. The better inhibitors in the buffer assay clustered among compounds in which the phenoxy group was substituted at the 3, 4, or 5 positions.

Chiral N,N-disubstituted trifluoro-3-amino-2-propanols are potent inhibitors of cholesteryl ester transfer protein.

A novel series of substituted N-benzyl-N-phenyl-trifluoro-3-amino-2-propanols are described that reversibly inhibit cholesteryl ester transfer protein (CETP). Starting with screening lead 22, various structural features were explored with respect to inhibition of the CETP-mediated transfer of [(3)H]cholesterol from high-density cholesterol donor particles to low-density cholesterol acceptor particles. The free hydroxyl group of the propanol was required for high potency, since acylation or alkylation reduced activity.