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New Spiro[Cycloalkane-Pyridazinone] Derivatives with Favorable Fsp3 Character

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New Spiro[Cycloalkane-Pyridazinone] Derivatives with Favorable Fsp3 Character Perspective New Spiro[cycloalkane-pyridazinone] Derivatives with Favorable Fsp3 Character Csilla Sepsey Für and Hedvig Bölcskei * Department of Organic Chemistry and Technology, University of Technology and Economics, Gellért tér 4, H-1111 Budapest, Hungary; [email protected] * Correspondence: [email protected] Received: 29 July 2020; Accepted: 21 September 2020; Published: 6 October 2020 Abstract: The large originator pharmaceutical companies need more and more new compounds for their molecule banks, because high throughput screening (HTS) is still a widely used method to find new hits in the course of the lead discovery. In the design and synthesis of a new compound library, important points are in focus nowadays: Lipinski’s rule of five (RO5); the high Fsp3 character; the use of bioisosteric heterocycles instead of aromatic rings. With said aim in mind, we have synthesized a small compound library of new spiro[cycloalkane-pyridazinones] with 36 members. The compounds with this new scaffold may be useful in various drug discovery projects. Keywords: Friedel–Crafts reaction; Grignard reaction; Fsp3 character; pyridazinones; spiro[cycloalkane-pyridazinone]; hydrazine 1. Introduction There are various methods used to find a hit that will later be a lead compound in the development of a new drug, a new chemical entity. Nowadays the most up-to-date methods are, e.g., computer aided drug design and the fragment-based techniques. High-throughput screening (HTS) [1,2] is a widely used method, which needs a large number of compounds. The large companies which are interested in the development of originator pharmaceutical products have their own molecule banks, with possible extensive compound libraries. In the building up of a compound library, the advantageous physicochemical parameters of the compounds, the so called ADME (absorption, distribution, metabolism, excretion) parameters, are very important aspects. Large companies do not allow one to put new compounds with disadvantageous parameters or with known toxicity into their molecule banks. After the publication of Lipinski’s “rule of five” (RO5) [3–5], more and more attention was paid to the physicochemical parameters of the drug candidate molecules. According to Lipinski’s rules, it is advantageous from the points of view of solubility and permeability if the number of H-bond donors is less than 5, the number of H-bond acceptors is less 10, the calculated logP (P = octanol–water partition coefficient, clogP) is under 5, and the molecular mass is lower than 500. LogP provides valuable information about the lipophilic/hydrophobic property of the molecule which strongly influences the absorption of the substance, its interaction with the receptor, its metabolism, and its toxicity. Later, other important properties were studied. Veber et al. [6] suggested that the polar surface area should be smaller than 140 A2 and the number of rotatable bonds should be ten or less in an ideal case. The fulfillment of these two criteria provides the opportunity for good oral bioavailability. Today these parameters are routinely studied to predict the drug candidates’ pharmacokinetics and ADME profiles [3]. Over the past decade there has been an increasing practice of creating structurally more complex molecules which are closer to natural materials and provide an opportunity to produce new types of compounds. Chemistry 2020, 2, 837–848; doi:10.3390/chemistry2040055 www.mdpi.com/journal/chemistry Chemistry 2020, 2, x 2 more complex molecules which are closer to natural materials and provide an opportunity to produce Chemistry 2020, 2 838 new types of compounds. Lovering et al. [7,8] defined the complexity with the saturation of molecules. Saturation allows the formationLovering etof al. molecules [7,8] defined with the more complexity complex with st theructures saturation and of the molecules. expansion Saturation of the allowsstructural the formationversatility ofof moleculesthe compounds with more without complex significant structures increases and the in molecular expansion weight. of the structural It was also versatility supposed of thethat compounds increasing withoutFsp3 character significant may increases improve inthe molecular physicochemical weight. It properties was also supposed of the molecules that increasing which Fspcontribute3 character to clinical may improve success. theLovering physicochemical and his coworkers properties [7,8] of introduced the molecules the definition which contribute of the Fsp to3 clinicalcharacter, success. which is Lovering an important and his parameter coworkers to characterize [7,8] introduced the drug-likeness. the definition Fraction of the Fsp of sp3 character,3 carbons whichmeans: is Fsp an3 important= number of parameter carbons with to characterize sp3 hybridization the drug-likeness. /total number Fraction of carbon of sp atoms.3 carbons Thousands means: Fspof compounds3 = number which of carbons reached with a phase sp3 hybridization of drug rese/archtotal (research number ofphase, carbon Phase atoms. I–III, Thousands drugs) were of compoundsselected from which GVK reached BIO Biosciences’ a phase of drugdatabase research and (researchanalyzed phase, by their Phase sp3 I–III,character. drugs) From were the selected data fromobtained, GVK it BIO was Biosciences’ concluded that database the average and analyzed Fsp3 character by their was sp3 0.36character. for research From compounds the data obtained, and it itincreased was concluded to 0.47 for that drugs. the average This growth Fsp3 character trend was was observed 0.36 for in research all phases compounds of drug research. and it increased The degree to 0.47of saturation for drugs. also This affects growth the trend physical was prop observederties in of all the phases compounds. of drug research.With increasing The degree sp3 character, of saturation the alsowater aff solubilityects the physical increases properties and the of melting the compounds. point decreases. With increasing This way, sp 3onecharacter, is more the likely water to solubility produce increasescompounds and which the melting have favorable point decreases. ADME This parameters way, one, which is more increases likely to producetheir chances compounds of becoming which haveclinical favorable candidates ADME [7,8]. parameters, which increases their chances of becoming clinical candidates [7,8]. M. Hansson et al.al. studied the relationship between molecular hit rates in HTS and molecularmolecular descriptors. They They established established that that ClogP ClogP and and Fsp Fsp3 had3 had the thelargest largest influences influences on the on hit the rate hit [9]. rate This [9]. Thisinspired inspired researchers researchers to synthesize to synthesize new newcompound compound withwith highhigh Fsp3 Fspcharacter.3 character. For example, For example, after aftera HTS a HTSstudy, study, Hirata Hirata and andcoworkers coworkers [10 developed [10 developed a new a new series series of ROR of RORγ inhibitors,γ inhibitors, which which was was guided guided by byFsp Fsp3 character3 character and and ligand ligand efficiency efficiency (LE). (LE). Both Both of of them them are are important important drug-likeness drug-likeness metrics. metrics. With With a careful design, the authors could improve the metabolic stability and reduce the CYPCYP inhibitioninhibition of their orallyorally eefficaciousfficacious RORRORγγ inhibitorsinhibitors (Scheme(Scheme1 1).). SchemeScheme 1.1. Development ofof aa newnew seriesseries ofof RORRORγγ inhibitorsinhibitors guidedguided byby LELE andand FspFsp33.. 3 M. H. Clausen et al. published another example for the synthesis of compounds with high FspFsp3 3 19 character [[10,11].10,11]. They established a librarylibrary ofof fluorinatedfluorinated FspFsp3-rich-rich fragmentsfragments forfor 19F-NMR based screening in fragment based drug discovery (FBDD), which is one of the most important methods of searching for a lead in drug discovery. The synthesized 115 fluorinatedfluorinated fragments gave valuable hits 19 against four diverse protein targetstargets inin 19FF-NMR NMR screening. screening. Normally, thethe 3D3D descriptorsdescriptors performperform better in lead-compound searches than 2D descriptors, 3 such as Fsp3 or logP. D. C.C. KomboKombo et al.al. [[12]12] showedshowed thethe importanceimportance of thethe 2D2D andand 3D3D molecularmolecular descriptors for clinical clinical success. success. They They studied studied the the MDL MDL Drug Drug Data Data Report Report (MDDR) (MDDR) database; database; the thecompounds compounds were were monitored monitored from from the the preclinical preclinical phase phase to to the the market. market. According According their their experience, experience, these shape-basedshape-based 3D3D molecularmolecular descriptorsdescriptors predicted predicted the the success success or or withdrawal withdrawal from from the the market market of of a 3 compounda compound at at preclinical preclinical or or Phase Phase I stageI stage better better than than logD logD or or Fsp Fsp. 3. J. H.H. Nettles Nettles and and coworkers coworkers [13 ][13] used used 2D and 2D 3D and molecular 3D molecular descriptors descriptors for target fishingfor target connecting fishing theconnecting chemical the and chemical biological and space. biological They comparedspace. They the compared 2D and 3D the molecular 2D and 3D descriptors molecular for descriptors prediction offorthe prediction biological of targets.the biological This method targets. was This based method on the
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