Colin M. Tice

The use of spirocyclic scaffolds in drug discovery

Owing to their inherent three-dimensionality and structural novelty, spiro scaffolds have been increasingly utilized in drug discovery. In this brief review, we highlight selected examples from the primary medicinal chemistry literature during the last three years to demonstrate the versatility of spiro scaffolds. With recent progress in synthetic methods providing access to spiro building blocks, spiro scaffolds are likely to be used more frequently in drug discovery.

Selecting the right compounds for screening: does Lipinski's Rule of 5 for pharmaceuticals apply to agrochemicals?

Large numbers of compounds are now available through combinatorial chemistry and from compound vendors to screen for lead-level agrochemical activity. The likelihood that compounds with whole-organism activity will be discovered can be increased if compounds with physicochemical parameters consistent with transport to the target site are selected for screening. Certain ranges of simple parameters (molecular mass, log P, hydrogen-bond donors and acceptors, rotatable bonds) have been correlated with oral bioavailability of drugs. The distribution of these parameters for commercial insecticides and post-emergence herbicides was examined and ranges consistent with whole-organism activity are proposed for the two classes of agrochemical. The most significant difference identified between drugs and these two classes of agrochemicals was the lower numbers of hydrogen-bond donors allowed in the latter cases. The frequency with which certain functional groups occur in drugs and agrochemicals was also compared.

INHIBITORS OF 11BETA-HYDROXYSTEROID DEHYDROGENASE TYPE 1

Carcinogenesis of hormone-related cancers involves hormone-stimulated cell proliferation, which increases the number of cell divisions and the opportunity for random genetic errors. In target tissues, steroid hormones are interconverted between their potent, high affinity forms for their respective receptors and their inactive, low affinity forms. One group of enzymes responsible for these interconversions are the hydroxysteroid dehydrogenases, which regulate ligand access to steroid receptors and thus act at a pre-receptor level. As part of this group, the 17β-hydroxysteroid dehydrogenases catalyze either oxidation of hydroxyl groups or reduction of keto groups at steroid position C17. The thoroughly characterized 17β-hydroxysteroid dehydrogenase type 1 activates the less active estrone to estradiol, a potent ligand for estrogen receptors. This isoform is expressed in gonads, where it affects circulating levels of estradiol, and in peripheral tissue, where it regulates ligand occupancy of estrogen receptors. Inhibitors of 17β-hydroxysteroid dehydrogenase type 1 are thus highly interesting potential therapeutic agents for the control of estrogen-dependent diseases such as endometriosis, as well as breast and ovarian cancers. Here, we present the review on the recent development of inhibitors of 17β-hydroxysteroid dehydrogenase type 1 published and patented since the previous review of 17β-hydroxysteroid dehydrogenase inhibitors of Poirier (Curr. Med. Chem., 2003, 10, 453). These inhibitors are divided into two separate groups according to their chemical structures: steroidal and non-steroidal 17β- hydroxysteroid dehydrogenase type 1 inhibitors. Their estrogenic/ proliferative activities and selectivities over other 17β-hydroxysteroid dehydrogenases that are involved in local regulation of estrogen action (types 2, 7 and 12) are also presented.

Synthesis and SAR of cis-1-Benzoyl-1,2,3,4-tetrahydroquinoline ligands for control of gene expression in ecdysone responsive systems

A library of 35 cis-1-benzoyl-2-methyl-4-(phenylamino)-1,2,3,4-tetrahydroquinolines was prepared. The compounds bore various substitutuents on the benzoyl ring, at the 4-position of the phenylamino ring and at the 6-position of the tetrahydroquinoline ring. The compounds were assayed for their ability to cause expression of a reporter gene downstream of an ecdysone response element in a mammalian cell line engineered to express the ecdysone receptor from Aedes aegypti. In general, compounds with small lipophilic substituents at the meta and para-positions of the benzoyl ring and hydrogen or fluorine at the 4-position of the phenylamino ring and the 6-position of the tetrahydroquinoline ring were the most potent.

Optimization of α-acylaminoketone ecdysone agonists for control of gene expression

Abstract Fifteen new α-acylaminoketones were prepared by four different routes in an initial effort to optimize the potency of these compounds as ecdysone agonists. The compounds were assayed in mammalian cells expressing the ecdysone receptors from Bombyx mori (BmEcR) and Choristoneura fumiferana (CfEcR) for their ability to cause expression of a reporter gene downstream of an ecdysone response element. A new α-acylaminoketone was identified which had activity equal to that of the standard dibenzoylhydrazine ecdysone agonist GS ™ -E in the assay based on CfEcR.

Discovery of VTP-27999, an Alkyl Amine Renin Inhibitor with Potential for Clinical Utility.

Structure guided optimization of a series of nonpeptidic alkyl amine renin inhibitors allowed the rational incorporation of additional polar functionality. Replacement of the cyclohexylmethyl group occupying the S1 pocket with a (R)-(tetrahydropyran-3-yl)methyl group and utilization of a different attachment point led to the identification of clinical candidate 9. This compound demonstrated excellent selectivity over related and unrelated off-targets, >15% oral bioavailability in three species, oral efficacy in a double transgenic rat model of hypertension, and good exposure in humans.

Structure-based design and synthesis of 1,3-oxazinan-2-one inhibitors of 11β-hydroxysteroid dehydrogenase type 1.

Structure based design led directly to 1,3-oxazinan-2-one 9a with an IC(50) of 42 nM against 11β-HSD1 in vitro. Optimization of 9a for improved in vitro enzymatic and cellular potency afforded 25f with IC(50) values of 0.8 nM for the enzyme and 2.5 nM in adipocytes. In addition, 25f has 94% oral bioavailability in rat and >1000× selectivity over 11β-HSD2. In mice, 25f was distributed to the target tissues, liver, and adipose, and in cynomolgus monkeys a 10 mg/kg oral dose reduced cortisol production by 85% following a cortisone challenge.

The Medicinal Chemistry of Liver X Receptor (LXR) Modulators

LXRs have been of interest as targets for the treatment of atherosclerosis for over a decade. In recent years, LXR modulators have also garnered interest for potential use in the treatment of inflammation, Alzheimers disease (AD), dermatological conditions, hepatic steatosis, and oncology. To date, no LXR modulator has successfully progressed beyond phase I clinical trials. In this Perspective, we summarize published medicinal chemistry efforts in the context of the available crystallographic data, druglikeness, and isoform selectivity. In addition, we discuss the challenges that need to be overcome before an LXR modulator can reach clinical use.

Regiocontrolled synthesis of 3-substituted-6-trifluoromethyl-4(3H)-pyrimidinones

Abstract Direct reaction of a variety of N -monosubstituted benzamidines with 4,4,4-trifluoroacetoacetate esters substituted at the 2-position with methyl, ethyl or methoxy afforded moderate to good yields of herbicidal 3-substituted-6-trifluoromethyl-4(3 H )-pyrimidinones. Lower yields were obtained with the corresponding 4,4-difluoroacetoacetate esters and the reaction failed with nonfluorinated β-ketoesters. In addition to benzamidines, 3- and 4-pyridylcarboxamidines reacted successfully. The reaction tolerated propyl, allyl, propargyl and phenyl substituents on the amidine nitrogen.

Spirocyclic ureas: Orally bioavailable 11β-HSD1 inhibitors identified by computer-aided drug design

Structure-guided drug design led to the identification of a class of spirocyclic ureas which potently inhibit human 11beta-HSD1 in vitro. Lead compound 10j was shown to be orally bioavailable in three species, distributed into adipose tissue in the mouse, and its (R) isomer 10j2 was efficacious in a primate pharmacodynamic model.