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as well as decreased metabolic stability. Interestingly, potency was slightly increased in cyclobutyl derivative 12; however, the analog was also unfavorable with respect to in vitro clearance. In some cases, the oxetanyl group has improved metabolic stability [38, 39] compared with related alkyl derivatives. Remarkably, the exchange of cyclobutyl for oxetanyl (compound 13) led to a 14‐fold higher stability in rat hepatocytes, but sGC stimulation was weaker than with derivative 10 or 12. Since the permeability across Caco‐2 cell monolayers was also very low (P _app A–B = 2 nm/s), combined with a high efflux ratio of 74, compound 13 was not pursued further. Additional efforts to improve the overall profile, by the introduction of fluorine or steric bulk (compounds 14 and 15), led to a slight increase in potency (MEC = 0.2 μM vs 0.3 μM for 10); however, metabolic stability was in all cases dramatically reduced.

Table 3.2 Properties of the N‐substituted methyl carbamates 1, 3–9.

Compound	R	cGMP formation MEC a (μM)	ClogD [37] pH 7.5	In vitro clearance (rat hepatocytes) CLb (l/h/kg)
1		0.03	1.99	0.2
3		0.2	2.29	0.7
4		0.3	1.52	3.7
5		0.1	2.21	0.4
6		0.1	2.48	0.9
7		0.1	3.15	3.2
8		0.2	3.20	3.2
9		0.7	3.29	2.4

      ^a MEC, minimal effective concentration to achieve stimulation of cGMP formation (≥3‐fold increase in basal luminescence) in a recombinant sGC‐overexpressing cell line [36].

Summing up, the carbamate portion of the analogs tolerates various substituents with respect to sGC stimulation but seems to be a crucial region for influencing metabolic stability. All our different strategies, introduction of steric bulk, polarity and substitution by fluorine seemed to offer no promising path forward for optimizing in vitro clearance. Still, the N‐unsubstituted carbamate 10 appeared to be optimally constructed in this respect. Thus, the focus of the optimization strategy was shifted away from the carbamate moiety and our next efforts were directed to the central scaffold and the identification of alternative cores that could lead to a potentially superior overall pharmacokinetic profile (modifications summarized in Table 3.4).

Table 3.3 Properties of the N‐H alkyl carbamates 10–15.

Compound	R	cGMP formation MECa (μM)	ClogD [37] pH 7.5	In vitro clearance (rat hepatocytes) CLb (l/h/kg)	Caco‐2 Papp A–B (nm/s) (Efflux ratio)
10		0.3	1.49	0.1	79 (5)
11		0.8	2.10	0.9	n.d.b
12		0.2	2.05	1.4	23 (25)
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