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Histone demethylase LSDl (KDMlA) belongs to the flavin adenine dinucleotide (FAD) dependent family of monoamine oxidases and is vital in regulation of mammalian biology. Dysregulation and overexpression of LSD1 are hallmarks of a number of human diseases, particularly cancers that are characterized as morphologically poorly differentiated. As such, inhibitors of LSD1 have potential to be beneficial as a cancer therapy. The most clinically advanced inhibitors of LSDl are covalent inhibitors derived from tranylcypromine (TCP). Herein, we report the discovery of a novel series of reversible and selective LSDl inhibitors. Exploration of structure-activity relationships (SARs) and optimization of ADME properties resulted in the identification of clinical candidate CC-90011. CC-90011 exhibits potent on-target induction of cellular differentiation in acute myeloid leukemia (AML) and small cell lung cancer (SCLC) cell lines, and antitumor efficacy in patient-derived xenograft (PDX) SCLC models. CC-90011 is currently in phase 2 trials in patients with first line, extensive stage SCLC (ClinicalTrials.gov identifier: NCT03850067).

The bromodomain and extra-terminal (BET) family of epigenetic proteins has attracted considerable attention in drug discovery given its involvement in regulating gene transcription. Screening a focused small molecule library based on the bromodomain pharmacophore resulted in the identification of 2-methylisoquinoline-1-one as a novel BET bromodomain-binding motif. Structure guided SAR exploration resulted in >10,000-fold potency improvement for the BRD4-BD1 bromodomain. Lead compounds exhibited excellent potencies in both biochemical and cellular assays in MYC-dependent cell lines. Compound 36 demonstrated good physicochemical properties and promising exposure levels in exploratory PK studies.

Using structure-based drug design, we identified and optimized a novel series of pyrimidodiazepinone PLK1 inhibitors resulting in the selection of the development candidate TAK-960. TAK-960 is currently undergoing Phase I evaluation in adult patients with advanced solid malignancies.

The azetidinone LY307174 (1) was identified as a screening lead for the vasopressin V1a receptor (IC50 45 nM at the human V1a receptor) based on molecular similarity to ketoconazole (2), a known antagonist of the luteinizing hormone releasing hormone receptor. Structure–activity relationships for the series were explored to optimize receptor affinity and pharmacokinetic properties, resulting in compounds with Ki values

A solution-phase, multi-reaction sequence has been developed for the parallel synthesis of ethanolamine libraries. This approach uses 2,3-dibromopropene as a template for the synthesis of a small olefin sub-library, which is then further functionalized to form the final ethanolamine library. The methodology is demonstrated by the synthesis of a 5×4 array of ethanolamines.

A method for the solid phase synthesis of urea libraries from primary and secondary amines is described which utilizes a thiophenoxy carbonyl linker. Sequential release of different urea products from a common batch of resin using a “milking” procedure has also been accomplished.

Using a combination of iterative structure-based design and an analysis of oral pharmacokinetics and antiviral activity, AG1343 (Viracept, nelfinavir mesylate), a nonpeptidic inhibitor of HIV-1 protease, was identified. AG1343 is a potent enzyme inhibitor (Ki = 2 nM) and antiviral agent (HIV-1 ED50 = 14 nM). An X-ray cocrystal structure of the enzyme-AG1343 complex reveals how the novel thiophenyl ether and phenol-amide substituents of the inhibitor interact with the S1 and S2 subsites of HIV-1 protease, respectively. In vivo studies indicate that AG1343 is well absorbed orally in a variety of species and possesses favorable pharmacokinetic properties in humans. AG1343 (Viracept) has recently been approved for marketing for the treatment of AIDS.

During the past several years, the field of combinatorial chemistry has expanded to include not only solid- and solution-phase methods for expedited compound synthesis, but also hybrid approaches that span these two extremes. In particular, polymer-supported reagents have emerged as useful combinatorial chemistry tools for the discovery and optimization of new pharmaceutical leads.

The synthesis of 2′,3′-dideoxy-3′-hydroxymethylcytidine 1 was accomplished using two different approaches. First, uridine and cytidine were used to prepare the key intermediate epoxides 15 and 31 which were opened with cyanide, deoxygenated by elimination to vinyl nitriles 17 and 36, and reduced by 1,4 hydride addition to the saturated nitriles 18 and 37. Secondly, a novel Rh-catalyzed hydroformylation reaction of 2′,3′-didehydro-2′,3′-dideoxycytidine 46 was used to prepare 1 in four steps. The attempted use of 2′-deoxyuridine and 2′-deoxycytidine to prepare 1 is also discussed.

Amines and acylated amines are synthesized in traditional solution phase reactions, then rapidly purified by ion exchange chromatography to yield pure products. In some instances, impurities devoid of ionizable functionality can be covalently modified prior to purification. The generic purification sequence is applicable to a variety of reactions, and is amenable to automation with commercially available equipment.

Solution phase parallel synthesis of equimolar mixtures of ureas was accomplished using a solid-supported “covalent scavenger” (aminomethylpolystyrene) to remove isocyanate impurities. Screening of these purified mixtures for antirhinoviral activity in a whole cell assay and subsequent deconvolution of hit mixtures afforded novel antirhinoviral agents with low cytotoxicities.

Solid supported nucleophiles and electrophiles are employed to expedite the work-up and purification of a variety of amine alkylations acylacylations. These solid suported scavengers are particularly advantageous for the construction of non-peptide libraries in a parallel array format.

An 800 compound hydantoin library has been constructed using a diverse set of 20 amino acids and over 80 primary amines. Amino acids were attached via their N-termini to hydroxymethyl polystyrene using a carbamate linker. Bound amino acids were converted to their corresponding amides and then cyclized under basic conditions to give hydantoins in high purities.

Peptide aldehydes have been synthesized and evaluated as inhibitors of human rhinovirus 3C protease. Those inhibitors containing a C-terminal glutamine aldehyde were prepared using newly developed methodology involving reduction of the corresponding glutarimide, which can be easily prepared from N-protected glutamine. Low molecular weight (

N-Cbz-(S-phenyl)-L-cysteine (3) has been prepared on a multi-kilogram scale in high yield and optical purity from the β-lactone of N-Cbz-L-serine.

The cocrystal structures of LY289612 and LY297135 were used as a starting point in the design of nonpeptidic HIV-1 protease inhibitors. This report details the discovery of a series of novel aromatic P 2 replacement groups. The 3-hydroxy-2-methyl benzoic acid group, discovered in AG1254, was incorporated into the hydroxyethyl amine series to produce the potent antiviral compound (LY309391/ AG1310).

Using the X-ray crystal structure of the inhibitor 1 complexed to HIV-1 protease, a new series of HIV-1 protease inhibitors was developed incorporating substituted isophthalic acid derivatives as amino acid surrogates. Through iterative structure-based design, the lead compound 2 was optimized to produce a variety of non-peptide HIV-1 protease inhibitors with significant antiviral activity. In contrast to 1, several members of this series exhibit significant oral absorption in animals.

Using information obtained from the co-crystal structure of an initial peptidomimetic lead complexed with HIV-1 protease, a series of inhibitors was constructed with substituents designed to span from the P1 to the P3 pockets of the enzyme. In accord with prediction, systematic extension of the P1 substituent with large, lipophilic groups leads to enhancements in binding potencies for this class of inhibitors. Surprisingly, inhibitors with large substituents at both P1 and P3 are also well-tolerated by the enzyme, providing compounds with subnanomolar binding affinities for HIV-1 protease.

A family of readily accessible Phe-Pro mimics has been devised in which ortho-substituted benzamides serve as proline surrogates. When suitably functionalized, these dipeptide isosteres afford potent inhibitors of HIV-1 protease which are also effective in whole cell antiviral assays.

The discovery of two classes of heterocyclic dipeptidyl peptidase IV (DPP-4) inhibitors, pyrimidinones and pyrimidinediones, is described. After a single oral dose, these potent, selective, and noncovalent inhibitors provide sustained reduction of plasma DPP-4 activity and lowering of blood glucose in animal models of diabetes. Compounds 13a, 27b, and 27j were selected for development.

N-Cbz-(S-phenyl)-L-cysteine (3) has been prepared on a multi-kilogram scale in high yield and optical purity from the β-lactone of N-Cbz-L-serine.

Using the X-ray crystal structure of the inhibitor 1 complexed to HIV-1 protease, a new series of HIV-1 protease inhibitors was developed incorporating substituted isophthalic acid derivatives as amino acid surrogates. Through iterative structure-based design, the lead compound 2 was optimized to produce a variety of non-peptide HIV-1 protease inhibitors with significant antiviral activity. In contrast to 1, several members of this series exhibit significant oral absorption in animals.

Peptide aldehydes have been synthesized and evaluated as inhibitors of human rhinovirus 3C protease. Those inhibitors containing a C-terminal glutamine aldehyde were prepared using newly developed methodology involving reduction of the corresponding glutarimide, which can be easily prepared from N-protected glutamine. Low molecular weight (

2′,3′-Dideoxy-3′-hydroxymethylcytidine (1) has been synthesized via stereoselective Rh-catalyzed hydroformylation of 2′,3′-didehydro-2′,3′-dideoxycytidine 3b. This synthesis incorporates the first successful hydroformylation of a nucleoside olefin.

During the past several years, the field of combinatorial chemistry has expanded to include not only solid- and solution-phase methods for expedited compound synthesis, but also hybrid approaches that span these two extremes. In particular, polymer-supported reagents have emerged as useful combinatorial chemistry tools for the discovery and optimization of new pharmaceutical leads.

The synthesis of 2′,3′-dideoxy-3′-hydroxymethylcytidine 1 was accomplished using two different approaches. First, uridine and cytidine were used to prepare the key intermediate epoxides 15 and 31 which were opened with cyanide, deoxygenated by elimination to vinyl nitriles 17 and 36, and reduced by 1,4 hydride addition to the saturated nitriles 18 and 37. Secondly, a novel Rh-catalyzed hydroformylation reaction of 2′,3′-didehydro-2′,3′-dideoxycytidine 46 was used to prepare 1 in four steps. The attempted use of 2′-deoxyuridine and 2′-deoxycytidine to prepare 1 is also discussed.

Solution-phase, parallel-synthesis techniques were used to optimize a series of nonbasic NK-1 antagonists, resulting in the identification of (R)-26, an orally bioavailable compound with subnanomolar potency.

Osmium tetraoxide has been demonstrated to be a highly efficient catalyst for the chemoselective oxidation of a variety of sulfides to the corresponding sulfones. Tertiary amine catalysis appears to play a key role in the reaction.

The absolute stereochemistry of the rutamycins has now been determined. This has been accomplished through an independent asymmetric synthesis of spiroketal, a known degradation product of rutamycins A and B

A convergent asymmetric synthesis of the antinoeplastic macrolide antibiotic cytovaricin has been achieved through the synthesis and coupling of the illustrated spiroketal and polyol glycoside subunits. All absolute steroechemical relationships within the target structure were ultimately controlled by the use of asymmetric aldol, alkylation, or epoxidation methodology. Union of the two subnits was accomplished by Julia-Lythgoe trans olefination, providing direct access to a suitable macrolactonization substrate

Alogliptin is a potent, selective inhibitor of the serine protease dipeptidyl peptidase IV (DPP-4). Herein, we describe the structure-based design and optimization of alogliptin and related quinazolinone-based DPP-4 inhibitors. Following an oral dose, these noncovalent inhibitors provide sustained reduction of plasma DPP-4 activity and a lowering of blood glucose in animal models of diabetes. Alogliptin is currently undergoing phase III trials in patients with type 2 diabetes.

Recent studies have demonstrated that selective 5-HT(1F) receptor agonists inhibit neurogenic dural inflammation, a model of migraine headache, indicating that these compounds may be effective therapies for the treatment of migraine pain. This communication describes the synthesis and discovery of a novel compound, N-[3-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl]-4-fluorobenzamide (4), which possesses high binding affinity and selectivity at the 5-HT(1F) receptor relative to more than 40 other serotonergic and nonserotonergic receptors examined.

Solution-phase, parallel-synthesis techniques were used to optimize a series of nonbasic NK-1 antagonists, resulting in the identification of (R)-26, an orally bioavailable compound with subnanomolar potency.

A solution-phase, multi-reaction sequence has been developed for the parallel synthesis of ethanolamine libraries. This approach uses 2,3-dibromopropene as a template for the synthesis of a small olefin sub-library, which is then further functionalized to form the final ethanolamine library. The methodology is demonstrated by the synthesis of a 5×4 array of ethanolamines.

The synthesis of allylic amine libraries derived from olefin templates is described. The two-step, solution phase reaction sequence consists of amination of the template followed by Suzuki coupling and expedited purification via ion exchange chromatography. The methodology has been used to synthesize a 1344-member allylic amine library.

2′,3′-Dideoxy-3′-hydroxymethylcytidine (1) has been synthesized via stereoselective Rh-catalyzed hydroformylation of 2′,3′-didehydro-2′,3′-dideoxycytidine 3b. This synthesis incorporates the first successful hydroformylation of a nucleoside olefin.