Table 4A, Target SAR Analysis for Compounds 1-20* - Probe Reports from the NIH Molecular Libraries Program

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Table 4ATarget SAR Analysis for Compounds 1-20^*

					Structure			Potency and Selectivity^†
								IC50 in vitro (nM) (AID 493154)	IC50 in situ (nM) (AID 504482)	% INH ABDH11 at given cpd conc. (AID 493111)			Anti-target(s)^‡ (AID 493111)			Fold Selectivity^§ ABHD11 vs. other SHs (AID 493111)
Entry	lab name	CID	SID	SRID	Regio-isomer	(R₁/R₂)^**	R₃	IC50 in vitro (nM) (AID 493154)	IC50 in situ (nM) (AID 504482)	30 nM	200 nM	1500 nM	30 nM	200 nM	1500 nM	Fold Selectivity^§ ABHD11 vs. other SHs (AID 493111)
1	HTS hit	735660	92709166	SR-01000625310-2	N1	morpholino	benzo^††	18	ND	100	100	100			LYPLA1 ESD APEH	>11
2	AA26-5	46829228	99205814	SR-02000000403-1	N1	morpholino	H	ND	ND	0	50	100				>7
3	AA34-1	46937239	99445324	SR-02000000944-1	N2	morpholino	Ph	ND	ND	100	100	100		ESD APEH	ESD APEH	7
4	AA34-2	46937228	99445325	SR-02000000945-1	N2	morpholino	3,5-difluoro Ph	ND	ND	100	100	100	APEH	ESD APEH	LYPLA1 ESD APEH	0
5	AA34-3	46937230	99445326	SR-02000000946-1	N2	morpholino	4-OCF₃ Ph	ND	ND	100	100	100			ESD APEH	>6
6	AA34-4	46937235	99445327	SR-02000000947-1	N2	morpholino	CPh₂OH	ND	ND	100	100	100		LYPLA1	LYPLA1 LYPLA2 ESD APEH	>1
7	AA26-9	46829232	99205818	SR-02000000407-1	N1	Piperidyl	H	ND	ND	0	50	100			LYPLA1	>1
8	AA40-1	46937232	99445331	SR-02000000951-1	N2	Piperidyl	CPh₂OH	ND	ND	100	100	100	LYPLA1	LYPLA1 LYPLA2 ESD	LYPLA1 LYPLA2 ESD APEH	0
9	AA40-2	46937234	99445328	SR-02000000948-1	N2	Piperidyl	4-PhOPh	ND	ND	50	100	100	ESD	LYPLA1 ESD	LYPLA1 ESD	0
10	AA40-3	46937227	99445329	SR-02000000949-1	N2	Piperidyl	6-OMe naphthal	ND	ND	50	100	100	ESD	ESD APEH	LYPLA1 LYPLA2 ESD APEH	0
11	AA47-1	46937241	99445330	SR-02000000950-1	N2	Piperidyl	CHPhOH	ND	ND	100	100	100	LYPLA1	LYPLA1 LYPLA2 ESD	LYPLA1 LYPLA2 ESD	0
12 (ML226)	AA44-1	56593112	99445332	SR-02000000952-1	N2	2-Et piperidyl	CPh₂OH	15	0.68	100	100	100			APEH	100
13	KLH31	46937238	99445333	SR-02000000953-1	N1	3-Bz piperidyl	CPh₂OH	ND	ND	100	100	100	LYPLA1 LYPLA2	LYPLA1 LYPLA2	LYPLA1 LYPLA2 ESD	0
14	AA44-3	46937244	99445334	SR-02000000954-1	N2	4-Me piperidyl	CPh₂OH	ND	ND	100	100	100	LYPLA1 LYPLA2	LYPLA1 LYPLA2 APEH	LYPLA1 LYPLA2 ESD APEH	0
15	AA49-1	46937233	99445335	SR-02000000955-1	N2	4-OMe piperidyl	CPh₂OH	ND	ND	100	100	100	LYPLA1	LYPLA1 LYPLA2	LYPLA1 LYPLA2 ESD	0
16	AA50-1	46937231	99445336	SR-02000000956-1	N2	4-Bz piperidyl	CPh₂OH	ND	ND	100	100	100	LYPLA1 LYPLA2	LYPLA1 LYPLA2	LYPLA1 LYPLA2 ESD	0
17	AA62-2	46937243	99445337	SR-02000000957-1	N2	4-CPh₂OH piperidyl	CPh₂OH	ND	ND	100	100	100	LYPLA1 LYPLA2	LYPLA1 LYPLA2	LYPLA1 LYPLA2	0
18 (ML211)	AA64-2	46937240	99445338	SR-02000000958-1	N2	4-tBu piperidyl	CPh₂OH	10	ND	100	100	100	LYPLA1 LYPLA2	LYPLA1 LYPLA2	LYPLA1 LYPLA2 ESD	0
19	AA69-1	46937229	99445339	SR-02000000959-1	N2	4-tBu piperidyl	Cyclohexan (1)ol	ND	ND	100	100	100	LYPLA1	LYPLA1 LYPLA2	LYPLA1 LYPLA2 ESD	0
20	AA69-2	46937237	99445340	SR-02000000960-1	N2	4-tBu piperidyl	2-PrOH	ND	ND	0	0	100		LYPLA1 LYPLA2	LYPLA1 LYPLA2	0

*: All compounds listed are synthetic compounds
†: Color scheme: green = active (IC50, inhibition data) or ≥5-fold selective (fold selectivity data)
grey = not determined (ND)
orange = one or more anti-target(s) with >50% INH
yellow = anti-targets(s) with 50% INH
‡: Anti-targets: platelet-activating factor acetylhydrolase type 2 (PAFAH2), esterase D/formylglutathione hydrolase (ESD), lysophospholipases 1 and 2 (LYPLA1 and LYPLA2), N-acylaminoacyl-peptide hydrolase (APEH)
§: Fold selectivity:
--If in vitro IC50 determined: fold selectivity = highest_conc(≤50% INH anti-target)/IC50_target
--If in vitro IC50 not determined: fold selectivity = highest_conc(≤50% INH anti-target)/lowest_conc(≥50% INH target);
--If highest_conc(≤50% INH anti-target) < lowest_conc(≥50% INH target) fold selectivity = 0
**: Naming scheme for combined R1/R2 substituents (all cyclic) includes N
††: Fused at 5-position of triazole; see structure in Table 3

From: Optimization and characterization of a triazole urea inhibitor for alpha/beta hydrolase domain-containing protein 11 (ABHD11): anti-probe for LYPLA1/LYPLA2 dual inhibitor ML211

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Table 4ATarget SAR Analysis for Compounds 1-20*

Table 4ATarget SAR Analysis for Compounds 1-20^*